Dissertations / Theses: 'Latent HIV'

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Andrews, Sophie Marie. "Adaptive immune evasion in clinically latent HIV infection." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:b7416aab-d345-48df-9194-797c62d7db47.

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HIV is a master of immune evasion, utilising a range of different techniques to not only survive the human immune system, but also mediate its eventual catastrophic decline. Understanding how HIV evades the adaptive immune response is paramount to developing effective treatments and vaccines. This thesis aimed to investigate three key ways in which HIV-1 and HIV-2 mediate immune evasion in the context of clinically latent infection. Chapter three summarises a study into selection pressure and mutation in the gp120 envelope gene in a narrow-source HIV-1 cohort of former plasma donors (FPDs) from China. This study further characterised the cohort, and identified specific mutations in the gene consistent with antibody and CTL-driven selection pressure. Chapter four describes an investigation into the downregulation of HLA-I mediated by primary isolates of HIV-1 and HIV-2 Nef. Nef-mediated HLA-I downregulation contributes to the evasion of CTL responses. In stark contrast to previous reports, no evidence for differential downregulation of HLA-A and HLA-B was detected, but primary isolates invariably showed reduced activity relative to laboratory-adapted and consensus variants. In performing this study, a number of limitations came to light regarding how bifurcate analyses are used to interpret flow cytometric data collected in studies of receptor modulation. A novel technique - SWARM - was therefore developed to address these limitations, and is described in chapter five. Chapter six aimed to address why CTL responses against HIV-2 Nef are rare, despite HIV-1 Nef being highly immunogenic. A series of in vitro (immuno)proteasomal processing assays revealed HIV-2 Nef is more extensively digested than HIV-1 Nef, but further experimentation is required to explain the difference in response. Finally, chapter seven briefly summarises a successful collaborative attempt to resolve the first ever crystal structure of HIV-2 Nef.

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Esmail, Hanif. "How latent is 'latent' tuberculosis? : the radiographic, transcriptional and immunological characterisation of subclinical tuberculosis in HIV infected adults." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/30658.

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Background: The central hypothesis of the thesis is that the neat division of tuberculosis (TB) into states of active disease and latent infection is an oversimplification and that the transition between latent and active TB involves passage through a subclinical phase of disease, which may be prolonged, during which pathology evolves. The primary aim of this thesis is to utilise [18F]-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (FDG-PET/CT) to identify and define intra-thoracic pathology consistent with subclinical TB in a cohort of asymptomatic adults diagnosed with latent TB at high risk of developing active TB (due to HIV co-infection) and then to identify transcriptional and immunological biomarkers that distinguish those with radiographic evidence of subclinical pathology. Such biomarkers may have future translational potential as tests more predictive of active TB compared to the currently available tests (tuberculin skin testing (TST) and interferon gamma release assays (IGRA)) and may also aid our understanding of the biology of TB. Methodology: Healthy HIV infected, ART naïve, adult outpatients living in an area with very high TB burden (Khayelitsha township, Cape Town, South Africa) were screened to identify 35 participants that were asymptomatic, with CD4 count ≥ 350/mm3, evidence of latent TB (by QuantiFERON Gold in tube (QFGIT)) and with no history of previous tuberculosis or evidence of current active TB. These participants had FDG-PET/CT performed and were then commenced on isoniazid preventive therapy (IPT) or standard TB therapy if clinically indicated and had repeat FDG-PET/CT following treatment. A number of additional groups of HIV infected and uninfected control participants with and without active TB were also recruited for blood sampling. Microarray, carried out on RNA extracted from whole blood, was used to identify differentially abundant transcripts between those with and without subclinical pathology. A 38-plex assay and ELISA covering a total of 45 analytes were then used to identify serological or QFGIT plasma biomarkers that distinguish those with and without subclinical pathology. Main Results: Parenchymal abnormalities in the 35 participants were evaluated in detail and interpreted in relation to the historical autopsy data and 28.6% were categorised as having evidence of subclinical TB pathology. Analysis of the whole blood microarray for these 35 participants along with 15 age, sex and CD4 count matched controls with clinical active TB identified 82 transcripts that clustered 80% of those with subclinical TB with active TB. Those with more metabolically active subclinical pathology, as determined by FDG uptake, clustered more effectively with clinical active TB. This signature was confirmed as specific to TB in HIV uninfected controls. Transcripts relating to the classical complement pathway and Fcγ receptor were found to be overabundant in subclinical and active TB in relation to those with latent TB with no evidence of subclinical pathology. Neutrophil related transcripts were over abundant only in clinical active TB, particularly in those that were smear positive. Network analysis of the 82 transcript signature, informed the selection of 45 soluble protein analytes. 10 analytes showed a significant difference in concentration between the 3 groups (active, subclinical and latent TB). IL-1α with a cut-off of 16.9 pg/mL and circulating immune complex (CIC) with a cut-off of 100.9 μg Eq/mL individually classified 50% and together 70% of those with subclinical TB as active TB. In addition when assessed across 5 stages of increasing disease activity by PET findings and smear status all 10 analytes showed a significant increasing trend. Conclusion: The utility of FDG-PET/CT a novel research tool in the study of latent TB in humans has been systematically evaluated for the first time in this thesis. It has allowed for the identification of pathology within the lungs consistent with subclinical TB not reliably identified on CXR. Microarray analysis of whole blood has contributed of our understanding of which biological process may be pertinent from the early subclinical stages of disease, suggesting that the classical complement pathway and overabundance of Fcγ receptor may be important. Furthermore, the approach has lead to the identification of transcriptional and serological biomarkers that distinguish those with subclinical pathology from those without. These biomarkers may have translational potential as more predictive diagnostic tests for active TB.

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SILVA, NETO Francisco Bernardino da. "Teste tuberculínio no diagnóstico da infecção latente pelo Mycobacterium tuberculosis em pessoas vivendo com HIV/AIDS em um hospital de referência no Estado da Paraíba." Universidade Federal de Pernambuco, 2015. https://repositorio.ufpe.br/handle/123456789/17702.

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O diagnóstico e o tratamento da infecção latente pelo Mycobacterium tuberculosis (ILTB) são indicados para grupos nos quais a prevalência da infecção latente é alta, em contactantes de casos novos de tuberculose (TB) e quando o risco de reativação é alto como em pessoas vivendo com HIV/AIDS (PVHA). Tanto o vírus da imunodeficiência humana (HIV) facilita a reativação da ILTB quanto o Mycobacterium tuberculosis contribui para a progressão da doença pelo HIV. O conhecimento acerca do diagnóstico e do tratamento da ILTB em PVHA torna-se fundamental visto que o Relatório Global de Controle da Tuberculose da Organização Mundial da Saúde (OMS) indica que as PVHA estão 26 a 31 vezes mais propensas a desenvolver TB ativa quando comparadas à população geral. Além disso, a taxa de letalidade da TB em PVHA é 3 vezes maior do que a observada na população geral. Apesar de suas limitações, o teste tuberculínico (TT) continua sendo a principal ferramenta de diagnóstico da ILTB, entretanto, isso não parece refletir no número de TT solicitados e realizados e, consequentemente, no número de tratamentos prescritos para ILTB. No Brasil, e em particular na Paraíba, os dados sobre a solicitação e realização do TT e acerca da prescrição do tratamento para ILTB são pouco conhecidos. Esse estudo objetivou verificar a frequência de solicitação e de realização (inoculação do derivado protéico purificado (PPD) e leitura) do TT, a frequência de TT reator e a frequência da prescrição do tratamento para ILTB e caracterizar as PVHA atendidas em serviço de referência em HIV/AIDS e TB no estado da Paraíba quanto a aspectos sociodemográficos e laboratoriais, no período de janeiro de 2009 a dezembro de 2013. Para obtenção dos dados, utilizou-se formulário padronizado, preenchido, retrospectivamente, a partir das informações contidas na primeira consulta registrada nos prontuários dos pacientes atendidos no período do estudo. Dos 3.191 pacientes incluídos na pesquisa, 2.303 (72,2%) tiveram o TT solicitado. Destes, 2.047 (89,0%) foram submetidos a realização do TT que compreendeu a inoculação do PPD e a leitura da induração. Dos 2.047 pacientes que tiveram o PPD inoculado e submetidos a leitura da induração, 90 (4,4%) pacientes tiveram o TT reator sendo o tratamento para ILTB prescrito para todos. Os resultados da pesquisa sugerem que há uma excelente adesão à solicitação do TT e à prescrição do tratamento para ILTB entre os profissionais médicos e baixa prevalência de ILTB no local do estudo. Outrossim, acessibilidade adequada para realização e boa compreensão por parte dos pacientes quanto a sua importância no contexto da atenção à saúde das PVHA garantiram a frequência elevada de realização do TT.
The diagnosis and treatment of latent infection with Mycobacterium tuberculosis (LIMTb) are given to groups in which the prevalence of latent infection is high, in contacts of new cases of tuberculosis (TB) and when the risk of reactivation is high as in people living with HIV/AIDS (PLHA). Both the human immunodeficiency virus (HIV) facilitates the reactivation of LIMTb as Mycobacterium tuberculosis contributes to the progression of HIV disease. The knowledge about the diagnosis and treatment for PLHA in LIMTb becomes critical as the Global Tuberculosis Control Report of the World Health Organization (WHO) indicates that PLHA are 26-31 times more likely to develop active TB compared the general population. In addition, the TB mortality rate PLHA is 3 times higher than that observed in the general population. Despite its limitations, the tuberculin skin test (TST) remains the primary diagnostic tool LIMTb, however, this does not reflect the number of TST ordered and carried out and, consequently, the number of prescription treatments for LIMTb. In Brazil, particularly in Paraiba, data on the application and realization of TST and for prescribing treatment for LIMTb are little known. Thus faces, this study aimed to verify the request frequency and achievement (inoculation of purified protein derivative (PPD) and reading of induration) of TST, the TST frequency of reactor and the frequency of prescription treatment for LIMTb and characterize the PLHA met in reference service on HIV/AIDS and TB in the state of Paraiba as the sociodemographic and laboratory aspects, from January 2009 to December 2013. To obtain the data, we used standardized form filled out retrospectively from information contained on the first visit recorded in the medical records of patients seen during the study period. Of the 3,191 patients included in the study, 2,303 (72.2%) had the TST requested. Of these, 2,047 (89.0%) underwent TST understood that inoculation of the PPD and the reading of induration. Of the 2,047 patients who had the PPD inoculated and subjected to reading of induration, 90 (4.4%) patients had TST reactor being treating LIMTb prescribed for everyone. The survey results suggest there is excellent adhesion to the request of the TST and prescription treatment for LIMTb among medical professionals and low prevalence of LIMTb in the study site. Likewise sufficient access for achievement and good understanding by patients and their importance in the context of attention to health of PLHA ensured the high frequency of TST realization.

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Hiener, Bonnie. "Genetic Characterisation of Persistent HIV-1 in Naïve and Memory CD4+ T-cells from Effectively Treated Individuals." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/29533.

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Identifying the cell populations of the HIV reservoir and understanding the mechanisms of viral persistence is necessary to achieve an effective cure. Publication 1 presented the Full-Length Individual Proviral Sequencing (FLIPS) assay - a method to sequence near-full-length HIV proviruses, allowing identification of genetically-intact and potentially replication-competent HIV-1. Using FLIPS, we showed genetically-intact proviruses are unequally distributed between naïve (TN), central (TCM), transitional (T-TM), and effector (TEM) memory CD4+ T-cells and identified TEM as an important source of genetically-intact proviruses that persist on ART. Publication 2 investigated the mechanisms that allow genetically-intact HIV proviruses to persist in TEM cells during ART. An in-depth characterisation of the proviral landscape withing TN and memory CD4+ T-cells isolated from 24 individuals on ART for 2-18 years revealed that the HIV-1 proviral landscape is different and changes with time on ART across the cell subsets. We found that genetically-intact HIV persists over time in TEM cells. We provided evidence that Nef plays a role in the persistence of genetically-intact HIV within TEM cells, likely through the downregulation of MHC-I. Publication 3 investigated whether the proviral landscape of peripheral blood (PB) and lymph node (LN) derived HIV-1 proviruses is influenced by differences in immune pressure. Using FLIPS, we identified genetically-intact HIV proviruses in LN derived TN and memory CD4+ T-cell subsets. We found that the HIV-1 reservoir is similar between PB and LN derived CD4+ T-cell subsets, in terms of size and genetic composition. Lastly, we showed that the similarities between the HIV reservoir in PB and LN derived TN and memory cells are likely due to free trafficking of the cell subsets between the sites. Overall, this study poses TEM cells as a key component of the HIV-1 reservoir of individuals on ART and suggests Nef as an attractive therapeutic target.

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Antunes, Aline Araújo. "Vigilância da Tuberculose Latente nas pessoas que vivem com HIV/aids em Ribeirão Preto - SP, 2012 e 2013." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/22/22133/tde-15022016-161844/.

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A TB é a principal doença oportunista a acometer as pessoas vivendo com HIV/aids (PVHA), sendo a coinfecção TB/HIV um importante desafio para os sistemas de saúde. O estudo objetivou descrever a vigilância da tuberculose latente nas PVHA acompanhadas pelos Serviços de Atenção Especializada ao HIV/aids (SAE) da rede municipal de saúde de Ribeirão Preto- SP, nos anos de 2012 e 2013. Trata-se de um estudo epidemiológico, descritivo, do tipo levantamento. Participaram 33 indivíduos que desenvolveram diagnóstico de tuberculose latente em 2012 e 2013, notificadas no Sistema de Informação \"Quimioprofilaxia TB\", e que viviam com HIV/aids, acompanhadas nos cinco SAE de rede pública municipal de Ribeirão Preto- SP. Para proceder à coleta de dados, inicialmente foi realizado um levantamento das PVHA diagnosticadas com tuberculose latente, a partir do número de indivíduos cadastrados no sistema de informação \"Quimioprofilaxia TB\". Posteriormente, foi utilizado um questionário estruturado contendo 30 questões do qual trabalhou-se com as seguintes seções: I - Dados sociodemográficos; II - Dados sobre o perfil clínico das PVHA - no momento do diagnóstico da TB latente; III- Dados sobre o controle da TB nas PVHA; IV- Dados sobre a situação, estratégias de acompanhamento e o desfecho da TB latente nas PVHA. O estudo foi desenvolvido a partir de fontes secundárias de informação: Sistema de Informação (SI) \"Quimioprofilaxia TB\"; Prontuário Clínico; Sistema Informatizado Hygia-Web e Sistema de Informação de Agravos de Notificação (SINAN). De forma complementar, com apoio de um roteiro específico foi realizada entrevista com o ator chave - coordenador do Programa Municipal de Controle da Tuberculose e do Programa de DST/aids/hepatites virais - com o intuito de caracterizar o cenário com enfoque na descrição das ações de prevenção e controle da TB nas pessoas com HIV/aids. A análise dos dados foi realizada por meio de técnica estatística descritiva. Dos 355 casos identificados no SI Quimioprofilaxia TB, 135 foram notificados em 2012 e 220 em 2013, sendo que 44 ocorrências envolviam as PVHA em seguimento na rede pública municipal de saúde, dos quais 21 (47,7%) pertenciam ao SAE \"C\". Foram excluídos 11 casos devido à não localização de prontuários clínicos e equívocos na classificação de indivíduos que não possuíam o diagnóstico de HIV/aids. Das 33 PVHA consideradas na amostra final do estudo, houve predomínio do sexo masculino (54,5%), faixa etária de 31 a 60 anos (72,7%), economicamente ativos e casados/ união estável (36,4%). Em relação ao perfil clínico, 75,8% tinham a aids como situação diagnóstica, faziam uso da TARV, porém apenas 30,3% tinham registros de retirada mensal de tais medicamentos. A contagem de células de proteção (TCD4+) e carga viral indicava estabilização do HIV/aids na maioria dos sujeitos. Quanto ao controle e desfecho da QT, a maioria (93,9%) dos pacientes realizou o tratamento na modalidade autoadministrada, sendo que 22 (66,7%) finalizaram o tratamento, mas observou-se uma taxa de abandono de 18,1%. Sendo a TB a principal doença oportunista a acometer e ser responsável pelo maior número de mortes associadas às PVHA, torna-se essencial a implementação de estratégias que favoreçam a vigilância da TB latente nas PVHA contribuindo como medida fundamental para o controle da doença ativa. A vigilância dos dados contribui para o planejamento e melhoria das ações e intervenções prestadas. Assim, desafios são lançados no que se refere à integração de ambos programas frente à importância da vigilância e manejo dos agravos no contexto das políticas públicas
TB is the main opportunistic infection to affect people living with HIV/AIDS (PLWHA), and TB/HIV coinfection is a major challenge for health systems. The study aimed to describe the monitoring of latent TB in PLWHA followed by HIV/AIDS Specialized Health Services Specialized (SHS) of Ribeirão Preto-SP, in the years 2012 and 2013. It was an epidemiological descriptive study. Were included 33 individuals who developed diagnosis of latent tuberculosis in 2012 and 2013, reported in the System Information \"TB chemoprophylaxis,\" and living with HIV/AIDS, followed by the five SHS municipal public health network of Ribeirão Preto-SP. For data collection, it was initially conducted a survey of PLWHA diagnosed with latent tuberculosis, from the number of individuals registered in the information system (IS) \"TB chemoprophylaxis.\" After, it was used a structured questionnaire containing 30 questions which were considered the following sections: I - Socio-demographic data; II - Data on the clinical profile of PLWHA - at diagnosis of latent TB; III - Data on the control of TB in PLWHA; IV Data on the situation, monitoring strategies and the outcome of latent TB in PLWHA. The study was developed from secondary sources of information: Information System \"TB chemoprophylaxis\"; Health Record; Computerized Hygia-Web system and Notifiable Diseases Information System (SINAN). As a complement, with the support of a particular script we interviewed the key actor - Municipal Program Coordinator for Tuberculosis Control and STD/AIDS - in order to characterize the scenario focusing on the description of the actions about prevention and control of TB in PLWHA. Data analysis was performed using descriptive statistics technique. Of the 355 cases identified in the IS chemoprophylaxis TB, 135 were reported in 2012 and 220 in 2013, with 44 occurrences involving PLWHA in the follow-up in the municipal public health system, of which 21 (47.7%) belonged to the SHS \"C\". Eleven cases were excluded due to non-location clinical records and errors in the classification of individuals who did not have the diagnosis of HIV/AIDS. Of the 33 PLWHA considered in the final study sample, there was a predominance of males (54.5%), aged 31-60 years (72.7%), economically active and married/common-law marriage (36.4%). Regarding the clinical profile, 75.8% had AIDS as a diagnostic situation, made use of ART, but only 30.3% had monthly removal of records of such drugs. The protective cell count (CD4 +) and viral load indicated stabilization of HIV/AIDS in most subjects. As for the control and outcome of QT, the majority (93.9%) of patients held in the self-administered treatment modality, with 22 (66.7%) completed the treatment but there was a dropout rate of 18.1 %. TB being the main opportunistic disease to affect and be responsible for more deaths associated with PLWHA, it is essential to implement strategies that enhance the surveillance of latent TB in PLWHA contributing as a key measure to control active disease. Surveillance data contribute to the planning and improvement of actions and interventions provided. So challenges are launched with regard to the integration of both programs forward the importance of surveillance and management of diseases in the context of public policy

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Ranganath, Nischal. "Oncolytic Viruses as a Potential Approach to Eliminate Cells That Constitute the Latent HIV Reservoir." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37355.

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HIV infection represents a major health and socioeconomic challenge worldwide. Despite significant advances in therapy, a cure for HIV continues to be elusive. The design of novel curative strategies will require targeting and elimination of cells that constitute the latent HIV-1 reservoir. However, such an approach is impeded by the inability to distinguish latently HIV-infected cells from uninfected cells. The type-I interferon (IFN-I) response is an integral antiviral defense mechanism, but is impaired at multiple levels during productive HIV infection. Interestingly, similar global impairments in IFN-I signaling have been observed in various human cancers. This led to the development of IFN-sensitive oncolytic viruses, including the recombinant Vesicular Stomatitis Virus (VSV 51) and Maraba virus (MG1), as virotherapy designed to treat various cancers. Based on this, it was hypothesized that IFN-I signaling is impaired in latently HIV-infected cells (as observed in productively infected cells) and that VSV 51 and MG1 may be able to exploit such intracellular defects to target and eliminate latently HIV-infected cells, while sparing healthy cells. First, using cell line models of HIV-1 latency, intracellular defects in IFN-I responses, including impaired IFN / production and expression of IFNAR1, MHC-I, ISG15, and PKR, were demonstrated to represent an important feature of latently HIV-infected cells. Consistent with this, the latently HIV-infected cell lines were observed to have a greater sensitivity to VSV 51 and MG1 infection, and MG1-mediated killing, than the HIV-uninfected parental cells. Next, the ability of oncolytic viruses to kill latently HIV-infected human primary cells was demonstrated using an in vitro resting CD4+ T cell model of latency. Interestingly, while both VSV 51 and MG1 infection resulted in a significant reduction in inducible p24 expression, a dose-dependent decrease in integrated HIV-1 DNA was only observed following MG1 infection. In keeping with this, MG1 infection of memory CD4+ T cells from HIV-1 infected individuals on HAART also resulted in a significant decrease in inducible HIV-1 gag RNA expression. By targeting an intracellular pathway that is impaired in latently HIV-infected cells, the findings presented in this dissertation highlight a novel, proof-of-concept approach to eliminate the latent HIV-1 reservoir. Given that VSV 51 and MG1 are currently being studied in cancer clinical trials, there is significant potential to translate this work to in vivo studies.

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Fong, Linda Ellen. "Data-Driven Analysis of Phospho-Signaling Network Responses Enables Latent HIV Infected T Cell Targeting." Thesis, Yale University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10957324.

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Viral latency remains the most significant obstacle to HIV eradication. Current clinical strategies aim to purge the latent CD4+ T cell reservoir by activating viral expression, but are undercut by the inability to clear the latent reservoir. We first evaluated co-drugging criteria in a quantitative manner to optimize viral expression. However, this approach faces many challenges; and thus, we proposed to identify and target dysregulated signaling pathways in latent HIV-infected cells to promote cell death as a novel approach for eradication. To identify how HIV latency and reactivation alter signal transduction pathways regulating cell death, we explored the acute signaling response of latent HIV-infected CD4+ T cells across in vitro human latency models using systems-level analyses. We measured phosphorylation of five signaling proteins (AKT, IKBa, ERK, p38, and JNK) after stimulation with T-cell activating agents or latency reversing agents in infected cells and uninfected cells. Using these phosphorylation signatures, we built data-driven statistical models that successfully classified infected and uninfected cells, demonstrating that latent infection alters signaling at a systems level. We further identified that the stress kinase pathways p38 and JNK exhibited elevated signaling in latently infected cells and could be targeted to specifically increase cell death, independent of HIV reactivation.

To work out the mechanisms by which latent and reactivating HIV alters cell death regulation, we further examined signaling of 31 proteins in single cells over 48 hours using mass cytometry. Mass cytometry provides measurements at single-cell resolution, enabling us to separate responses in cells with latent versus reactivating HIV based on viral expression. We used conditional density-based analysis of the single-cell data to quantify the strength of signaling activity along different pathways. We discovered that latent and HIV-expressing cells are sensitized to apoptotic cell death via activation of p38-p53 signaling and inhibition of AKT/mTOR signaling. We identified a novel interaction in infected cells, in which increased p38 signaling activates the pro-death activity of the protein BAD, leading to increased apoptosis. Finally, we show in vitro that p38 and AKT/mTOR pathways can be simultaneously targeted to deplete the latent reservoir by preferentially killing latently infected cells without viral activation. Overall, we demonstrate that targeting altered phosphorylation signatures of latent HIV-infected cells provides a novel and effective strategy for latent HIV eradication.

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Kunze, Christine [Verfasser], and Ruth [Akademischer Betreuer] Brack-Werner. "Strategien zur Inhibierung der HIV-Reaktiverung in latent infizierten Astrozyten / Christine Kunze ; Betreuer: Ruth Brack-Werner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1150159189/34.

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Valencia, Celina I., and Celina I. Valencia. "Modeling social factors of HIV risk in Mexico." Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/625554.

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Background: Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS) is an urgent public health issue in Mexico. Mexico has witnessed a 122% increase in reported prevalence of HIV since 2001 (Holtz et al., 2014). Country estimates suggest there are between 140,000-230,000 individuals living with HIV in Mexico (CENSIDA, 2014). While approximately 50% of individuals living with HIV in Mexico are unaware that they are living with the virus (CENSIDA, 2014). Despite a federal universal HIV program implemented in 2011, HIV in Mexico has not reached a chronic infectious disease status as seen in other regions of the globe (Deeks, 2013). The mortality rate among individuals with HIV/AIDS in Mexico is 4.2 per 100,000 (CENSIDA, 2014). There is a paucity of findings regarding social and epidemiological data focused on populations outside traditional at risk populations of HIV in Mexico (Martin-Onraët et al., 2016). Analyzing aggregate country level data for Mexico provides necessary insights to better understanding previously unconsidered social factors that are informing sexual and reproductive health trends influencing HIV health patterns. Methods: Secondary analyses were performed on Mexico's Encuesta Nacional de Salud y Nutrición 2012 (ENSANUT). Mexico’s ENSANUT is a probabilistic aggregate national dataset with a multistage stratified cluster sampling design (Janssen et al., 2013). ENSANUT is Mexico’s equivalent to the National Health and Nutrition Examination Survey (NHANES) in the United States. Data is collected via self-report interviews conducted at the participant's home. A structured questionnaire was administered to individuals 20 years of age and older (≥ 20) where sexual and reproductive data was collected from participants. The ENSANUT adult study sub-sample (n=46,227) is comprised of 42.75% men and 57.25% women. A general linear model (GLM), principal component analysis (PCA), chi-squares (χ²), and logistic regressions were applied to the study adult subsample to disentangle social factors associated with sexually transmitted infections (STIs) in the population. Quantitative analyses were conducted on SAS 9.4. Findings: Men were more likely to have a STI diagnosis (OR=3.60; 95% CI 3.00, 4.32, p=<0.001). Previous HIV testing was found to be protective for STI diagnosis across both genders (OR=0.82, 95% CI 0.72, 0.94, p=<0.001). Co-infections of HIV/gonorrhea and HIV/syphilis (n=20) were the highest in the study population. The latent variable model indicates mental health and access to health care resources are critical for positive sexual and reproductive health outcomes in Mexico. Mental health was found to be non-protective for STI risk among the study population (OR=1.59, 95% CI 1.41, 1.81, p=<0.0001). Policy recommendations: 1. Increased access and utilization of HIV resources and mental health services would benefit the study population. Further qualitative research is needed to better understand the barriers to health care access and utilization in these two domains; 2. Increase in preventative programs and health initiatives that encourage established strategies for positive sexual and reproductive health outcomes. These strategies include: universal human papillomavirus (HPV) vaccines, wide availability of Pre-Exposure Prophylaxis (PrEP), and routine HIV/STI screenings; 3. Alternative data collection strategies for ENSANUT which are culturally appropriate for sexual and reproductive health constructs.

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O'Loughlin, Christina. "Evaluation of measurement quality in the assessment of health related issues using structural equation modelling techniques." Thesis, University of Ulster, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342424.

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Matsui, Hiroyuki. "CAGE-seq reveals that HIV-1 latent infection does not trigger unique cellular responses in a Jurkat T cell model." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/265190.

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Picone, Camila de Melo. "Avaliação da taxa de acesso à prescrição médica do tratamento preventivo de tuberculose com isoniazida em serviço especializado de HIV/aids." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5134/tde-02062014-153526/.

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Introdução: O Tratamento Preventivo com Isoniazida (TPI) é indicado para os pacientes com HIV/aids e infecção latente por Micobacterium tuberculosis (ILMTb) para os quais não haja contraindicação à Isoniazida. Entretanto, barreiras de acesso podem impedir que os pacientes realizem este tratamento. Objetivos: O presente estudo avaliou a taxa de acesso à prescrição médica do TPI em sujeitos com HIV/aids e ILMTb em seguimento em um serviço especializado de HIV/aids no período de fevereiro de 2005 a dezembro de 2009. Para os sujeitos que não tiveram acesso à prescrição do TPI, buscou-se, em prontuário, justificativas para esta conduta. Também foi identificado o perfil epidemiológico, clínico e demográfico dos sujeitos com HIV/aids e ILMTb e foi descrita a característica do médico que solicitou o teste tuberculínico (TT) e do que prescreveu o TPI. Métodos: No período de 02 de fevereiro de 2005 a 31 de dezembro de 2009 que estavam em seguimento no SEAP HIV/Aids foram incluídos sujeitos com HIV/Aids e ILMTB, diagnosticada através do Teste Tuberculínico (TT). Informações referentes às variáveis analisadas foram coletadas nos prontuários médicos e através de consulta ao Sistema de Informação e Gestão Hospitalar (SIGH) - Módulo Farmácia. Resultados: Foram incluídos 238 sujeitos dentre os 310 que tiveram TT > 5 mm no período do estudo. Destes, 70,6% (168) eram do sexo masculino; a média de idade foi de 42,6 anos; 88,2% (210) dos sujeitos tiveram acesso à prescrição do TPI. O acesso à prescrição do TPI foi associado à idade, ao tamanho da resposta ao TT, ao nadir de Linfócitos TCD4+ dos sujeitos em TARV e à presença de cicatriz de BCG. Sujeitos mais jovens, com resposta ao TT igual ou maior do que 10 mm e com cicatriz de BCG tiveram maior acesso à prescrição do TPI. Uma das questões a ser explorada em futuros estudos se refere aos fatores que influenciam, ou não, a decisão do profissional de introduzir este tratamento na situação em que o mesmo está recomendado tecnicamente. Conclusão: Os sujeitos mais jovens, com melhor situação imunológica de base, maior valor de resposta ao TT e com presença da cicatriz de BCG, tiveram maior acesso ao TPI. Neste estudo foi evidenciada a necessidade de que as instituições de saúde invistam em educação continuada de seus profissionais para elevarem a cobertura de ações programáticas, como é o tratamento da ILMTB, previsto nos programas nacionais de tuberculose e de HIV/aids. Além disso, é necessário que as equipes interdisciplinares atuem de forma integrada e harmônica, para garantir o acesso às ações de saúde. É possível identificar, porém muitas barreiras que restam para a serem rompidas de modo que os cidadãos que vivem com HIV/aids tenham acesso a este e aos demais tratamentos de que tenham necessidade
Background: Isoniazid Preventive Treatment (IPT) is recommended for patients with HIV/AIDS and Latent Infection by Mycobacterium tuberculosis (ILMTb) and no contraindication to isoniazid. However, access barriers may prevent patients to undergo to this treatment. Objectives: This study evaluated the rate of access to the prescription of IPT in subjects with HIV/aids and ILMTb followed up in a specialized HIV/aids from February 2005 to December 2009. For subjects who did not have access to the prescription of IPT, we sought, on records, justification for this conduct. Also, the epidemiological, clinical and demographic profile of individuals with HIV/AIDS and ILMTb and the characteristic of the doctor who requested the tuberculin skin test (TST) and prescribed IPT were identified. Methods: from 02 February 2005 to 31 December 2009 subjects followed up at SEAP HIV/aids with HIV/aids and ILMTB, diagnosed by Tuberculin Test (TST) were included. Information was collected from the medical records and from the Hospital Information and Management System (SIGH) - Pharmacy Module. Results: 238 subjects were included, among the 310 who had TST > 5 mm during the study period. Of these, 70.6 % (168) were male and the average age was 42.6 years, 88.2 % (210) had access to the prescription of IPT. Access to IPT prescription was associated with age , size of response to TST, nadir of lymphocytes CD4 + in subjects on ART and presence of BCG scar: younger subjects with response to TST equal to or greater than 10 mm and BCG scar had higher access rate to IPT prescription. An issue to be explored in the future refers to variables that influence the professional\'s decision to prescribe this treatment when it is technically recommended. Conclusion: younger subjects with better immune status at baseline, greater response to TST and presence of BCG scar, had more access to IPT. This study highlighted the need of educational programs for health professionals, in order to improve the coverage of activities devoted to reduce morbidity and mortality in HIV/aids patients, as is the treatment of ILMTB, recommended in national tuberculosis and HIV/AIDS programs. Furthermore, it is crucial, for interdisciplinary health teams, to operate in an integrated and harmonious way, to ensure, for HIV/aids patients, a healthy and longer life

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Devlin, Kathryn Noel. "EMPIRICALLY IDENTIFIED NEUROPSYCHOLOGICAL SUBTYPES IN HIV INFECTION: IMPLICATIONS FOR ETIOLOGY AND PROGNOSIS." Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/521261.

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Psychology
Ph.D.
Heterogeneity in the profile of HIV-associated neuropsychological disorder (HAND) may obscure understanding of its etiology and prognosis. Despite longstanding acknowledgement of this heterogeneity, HAND diagnostic approaches such as the Frascati criteria characterize neuropsychological function based on the level of impairment, without regard to the pattern of strengths and weaknesses. Attention to these patterns may enhance etiologic and prognostic specificity. We used latent class analysis (LCA) to identify relatively homogeneous subtypes of neurocognitive function in adults with well-treated HIV infection. We compared the diagnostic agreement of latent classes and Frascati categories, as well as their associations with demographics, HIV markers and antiretroviral factors, comorbid medical and psychiatric conditions, and everyday functioning. LCA identified four classes, whose cognitive profiles are depicted in Figure 1: cognitively intact, mild-to-moderate motor/speed impairment, mild-to-moderate memory/visuoconstruction impairment, and moderate mixed impairment. Latent classes and Frascati categories demonstrated good agreement in the overall classification of impaired cognition but more disagreement regarding subtypes of impairment. Both latent classes and Frascati categories demonstrated unique associations with etiologic factors and significant associations with functional outcomes. However, only latent classes, not Frascati categories, were associated with HIV variables. Additionally, functional difficulties were significantly elevated in the motor impairment class but not the memory impairment class despite similar levels of cognitive impairment in the two groups. Findings support the utility of a diagnostic approach that accounts for both the level and pattern of neurocognitive impairment. Future research should examine the neuropathological mechanisms, longitudinal trajectories, and treatments of empirically identified HAND subtypes.
Temple University--Theses

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Bouchat, Sophie. "Etude de la levée de la latence du virus HIV-1 et du potentiel thérapeutique associé." Doctoral thesis, Universite Libre de Bruxelles, 2014. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209220.

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Reuse, Sophie. "Etude de la réactivation de l'expression des provirus HIV-1 latents par la prostratine en synergie avec des inhibiteurs de désacétylases: mécanismes moléculaires impliqués et potentiel thérapeutique." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210213.

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L’infection par HIV-1 représente un des problèmes de santé publique majeurs de notre société actuelle. Le traitement HAART (Highly Active AntiRetroviral Therapy) inhibe le cycle réplicatif viral mais ne permet pas l’éradication du HIV-1. La principale cause de cet échec thérapeutique est la persistance de réservoirs cellulaires infectés de manière latente par HIV-1, qui, lors de l’arrêt du traitement HAART, sont à l’origine d’un rebond de la charge plasmatique virale. Le défi actuel est donc de découvrir de nouvelles méthodes d’élimination des cellules réservoirs. Une des stratégies envisagées est de forcer l’expression virale dans les cellules infectées de manière latente afin d’entraîner leur destruction suite à leur détection par le système immunitaire ou suite aux effets cytopathiques viraux. Parallèlement, le traitement HAART serait maintenu afin de limiter la propagation des virions néo-synthétisés. Plusieurs éléments sont impliqués dans la répression transcriptionnelle associée à la latence post-intégrationnelle du virus HIV-1 :la nature du site d’intégration ;l’absence de facteurs cellulaires inductibles tels que NF-κB ;la structure chromatinienne du provirus et les modifications post-traductionnelles des histones ;l’absence de niveaux suffisants de la protéine trans-activatrice Tat. De plus, notre laboratoire a précédemment mis en évidence un lien entre deux de ces éléments, en démontrant, dans une lignée modèle de latence post-intégrationnelle, que la cytokine pro-inflammatoire TNFα, un activateur de la voie de signalisation NF-κB, permet une réactivation synergique de l’expression virale combinée à l’inhibiteur d’histone-désacétylases (HDACI) TSA. Cependant, l’utilisation thérapeutique du TNFα et de la TSA est inenvisageable en raison de leurs toxicités.

\
Doctorat en Sciences
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Finestone, Michelle. "An Evaluation of a theory-based support group intervention for children affected by maternal HIV / Aids." Thesis, University of Pretoria, 2013. http://hdl.handle.net/2263/40207.

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The aim of this study was to evaluate a 24-week support group intervention programme which was designed to enhance adaptive behaviour of latent-phase children affected by maternal HIV/Aids. The meta-theoretical paradigms underlying the study were pragmatism and realism. The study was embedded in a concurrent nested (QUALquan) mixed-method design. The quantitative approach in the main study followed a quasi-experimental research design whereas the qualitative approach in this study, contributing to the largest part of the analysis in the study, followed a nested multiple case study design. The theory-driven outcome programme evaluation model applied in this study was the integrative process/outcome evaluation approach. The participants (n=139) were purposefully selected from among previously identified HIV-positive women (n=220) with children between the ages of 6 and 10 years at clinics in the Tshwane region, South Africa. Data were collected over a period of five years in multiple waves of intervention implementation. Prolonged, in-depth engagement by the researcher with participants was prioritized. The data collection strategies comprised of mother-and-child psychological questionnaires, group process notes, careworker focus groups, quality assurance questionnaires and field notes. The data were quantitatively analysed by means of a paired-sample t-test for within-group comparisons and descriptive statistics were furthermore applied. The qualitative text and narration obtained through the interviews, documents and focus groups were coded and analysed for themes. The themes of the emergent concepts were re-coded to establish improved defined categories. The different data sampling strategies assisted the researcher in triangulating the data for increased evaluation reliability. The PhD-study was conducted within a broader longitudinal study on resilience in South African mothers and children affected by HIV/Aids – the Promoting Resilience in Young Children Study. The findings of the Child Support Group Evaluation Study (e.g. PhD) showed that the content, methods and processes employed in the group-based sessions were effective and culturally sensitive. The intervention sessions enhanced the children’s coping skills, internalised and externalised behaviour and daily living, communication and socialisation skills. The group provided a buffer for the children and supported them in coping with their mothers’ illness. The children displayed normative values through their religious coping styles, their quest for and display of respect and their unambiguous assertion of right and wrong. A specific finding of this study was that the children created a sphere or space in which to order their thoughts, behaviours and emotions within the intervention. This provided them with parameters in their adverse circumstances to display adaptive behaviour or resilience which they could use to function adequately. The study suggests that the use of support groups should be incorporated into intervention programmes dealing with latent-phase children affected by HIV/Aids.
Thesis (PhD)--University of Pretoria, 2013.
gm2014
Educational Psychology
unrestricted

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Herzer, ThaÃs LÃbo. "InfecÃÃo latente por mycobacterium tuberculosis em portadores de infecÃÃo por HIV/AIDS: anÃlise atravÃs do uso de teste tuberculÃnico e teste de liberaÃÃo de interferon-gama." Universidade Federal do CearÃ, 2012. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=7821.

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As pessoas vivendo com HIV tÃm probabilidade aumentada de desenvolver, apresentar formar graves, ter cepas multirresistentes e morrer por tuberculose. A profilaxia para infecÃÃo latente por Mycobacteium tuberculosis (ILTB) diminui a chance de ativaÃÃo de tuberculose (TB) numa mÃdia de 62% nessa populaÃÃo. Entretanto, o diagnÃstico da TB na sua forma latente Ã controverso. O teste tuberculÃnico (TT) Ã o Ãnico exame aprovado no Brasil para avaliaÃÃo dessa infecÃÃo, embora existam problemas tanto na sua realizaÃÃo quanto na sua interpretaÃÃo. Exames de liberaÃÃo de interferon-gama foram criados recentemente com o objetivo de aumentar a especificidade e a praticidade da investigaÃÃo da ILTB. Esse estudo se propÃs a avaliar como vem sendo feita a investigaÃÃo da ILTB e o desempenho do TT e do QuantiFERON-TBÂ Gold In-Tube (QTF-GIT) em portadores de HIV. Foram selecionados ao todo 351 pacientes portadores de HIV e sem evidÃncia de TB ativa, admitidos em dois centros de referÃncia de Fortaleza-CE, no perÃodo de 2007-2010. Na admissÃo, 41,8% dos pacientes realizaram TT, 36,3% foram avaliados quanto a contato com TB e 28,4% tiveram radiografia de tÃrax. A profilaxia foi realizada para 73,3% dos pacientes com TT positivo. Houve diagnÃstico de ILTB em 25,3% dos pacientes de acordo com o TT e em 6,7% pelo QTF-GIT (p<0,001). A correlaÃÃo entre os resultados dos dois testes foi considerada fraca (k= -0,037). Resultado positivo do TT esteve associado com drogadiÃÃo (OR 7 CI: 1,53-32,11; p=0,01), contato com TB bacilÃfera (OR 13 CI: 2,7-62,83; p=0,001), profilaxia para ILTB prÃvia (OR 17,5 CI: 3,4-90,4; p<0,001), procedÃncia do interior do estado (OR 2,74 CI:1,04-7,22; p= 0,04). NÃo houve associaÃÃo entre QTF-GIT positivo e fatores de risco para TB. A mÃdia de contagem de linfÃcitos T CD4+ nos indivÃduos com TT positivo foi superior Ã mÃdia dos com TT negativo (535,8 vs. 373,4 cÃl/mm3; p=0,006), enquanto o inverso ocorreu em relaÃÃo ao QTF-GIT (277 vs. 438,3 cÃl/mm3; p= 0,055). A mÃdia do logaritmo da carga viral foi superior naqueles com QTF-GIT positivo (4,81 vs. 2,11 log10 cÃp/ml; p= 0,005). Mais da metade dos pacientes nÃo realizou TT, apesar da alta prevalÃncia de ILTB. O TT contou com maior nÃmero de testes positivos. O QTF-GIT mostrou-se superior para pacientes com elevada viremia e imunossupressÃo. Sugere-se o uso de ambos os testes de forma complementar para aumentar a chance de diagnÃstico de ILTB e diminuir os riscos de progressÃo da doenÃa.
People living with HIV have an enhanced chance to develop and to die of tuberculosis (TB). Many studies demonstrate that chemoprophylaxis for latent tuberculosis infection (LTBI) reduces the progression to active TB. Indeed, the diagnosis of LTBI is controversial. In Brazil, the only test approved for use is the tuberculin skin test (TST), however, this test is complicated by several problems due to application and interpretation of the exam. Recently developed interferon-gamma release assays (IGRA) using Mycobacterium tuberculosis-specific antigens have the advantage of decreased cross-reactivity and, therefore, increased specificity. The purpose of this study is to evaluate the adherence of LTBI diagnosis and to compare the results of the QuantiFERON-TBÂ Gold In-Tube test (QTF-GIT) and TST in a population of HIV-positive individuals from a country with high prevalence of TB. A cross-sectional study was carried out with 351 HIV patients without active tuberculosis, attending outpatient in two reference centers, from November 2007- 2010. At admission, 41.8% had realized TST, 36.3% had been interrogated about TB exposure and 28.4% had performed a chest X-ray. Chemoprophylaxis was offered to 73.3% of TST positive patients. The TST and QTF-GIT results were positive in 25.3% and 6.7% (p<0.001) of the individuals, respectively. The agreement between the two tests was poor (k= -0.037). Drug use (OR 7, 95% CI 1.5-32.1; p=0.01), TB exposure (OR 13, 95% CI 2.7-62.83; p=0.001), previous LTBI prophylaxis (OR 17.5, 95% CI 3.4-90.4; p<0.001), and living outside the state capÃtal (OR 2.7, 95% CI 1-7.2; p= 0.04) were associated with a positive TST result. There is no association between QTF-GIT positive result and risk factors for TB. TST positive individuals had a higher mean CD4+ cell count than those with TST negative result (535.8 cell/mm3 vs. 373.4 cell/mm3; p=0.006), in contrast to QTF-GIT positive result (277 cell/mm3 vs. 438.3 cell/mm3; p= 0.055). Higher viral load was associated with QTF-GIT positive result (4.8 log10 cop/ml vs. 2.1 log10 cop/ml; p= 0.005). Despite of Brazil being a country with a high burden of TB, more than half the patients have not realized TST, which appears to be more sensitive than QTF-GIT for diagnosis of LTBI. Otherwise, QTF-GIT shows better results in patients with advanced immunosuppression and high viral load. We suggest the use of both tests to increase LTBI diagnosis and decrease the risk of disease progression.

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Wyndham-Thomas, Chloe. "Screening for latent M. tuberculosis infection in HIV-positive patients residing in low tuberculosis incidence settings: Investigation of the current practices and identification of clinical- and immune-based strategies for improvement." Doctoral thesis, Universite Libre de Bruxelles, 2016. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/241270.

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Tuberculosis (TB) remains the main cause of death in people living with HIV (PLHIV). Indeed, PLHIV have a 20-30% greater risk of developing TB compared to HIV-uninfected subjects and have lower TB treatment success rates. In 2014, among the 9.6 million incident cases of TB reported worldwide, 12% occurred in PLHIV and 0.4 million deaths from HIV-associated TB were recorded.Mycobacterium tuberculosis is the main etiological agent for TB. For a majority of individuals, the immune response upon infection by M. tuberculosis is sufficient to prevent the development of disease, but insufficient to clear the bacteria. This leads to the persistence of viable M. tuberculosis in diverse cells with no resulting clinical manifestations, an entity known as latent tuberculosis infection (LTBI). The resulting reservoir of M. tuberculosis is vast, and an estimated one third of the world population is concerned. For subjects with LTBI, the life-time risk of reactivation and progression to TB lies between 5 and 10%. However, if co-infected with HIV, the risk is much greater and reaches 10% per year. According to a Cochrane review in 2010, the screening and treatment of LTBI in PLHIV reduces this risk by 30-60%. This prevention strategy is therefore widely recommended. However, the implementation of LTBI screening and treatment into standard HIV-care has been limited. In this work, three different approaches have been used to understand and address this issue, focusing on a low TB-incidence and high-income setting.The first approach was to assess the implementation of LTBI screening in HIV-care across Belgium and identify its barriers as perceived by the caregivers on the field. Raising awareness to this issue was an indirect objective of the study. A multi-choice questionnaire was sent to 55 physicians working in a Belgian AIDS reference center or satellite clinic. A response rate of 62% was obtained. Only 20% of participants performed LTBI screening on all their patients and notable variations in the screening methods used were observed. A large majority of participants were in favor of targeting LTBI screening to HIV-infected patients at highest risk of TB rather than a systematic screening of all PLHIV. These results have been communicated to the Belgian LTBI working group, currently updating the national LTBI screening guidelines. Indeed, targeting screening to those at highest risk of TB is an attractive strategy in low-TB incidence countries and is already recommended in the United Kingdom. However, to date, no score assessing the risk of TB in PLHIV has been validated. Among the barriers to LTBI screening identified by the participants of this first study, the most frequently reported were lack of sensitivity of screening tools, risk associated to polypharmacy and toxicity of treatment. Improving the sensitivity of LTBI screening was the cornerstone of the second approach. The available screening tools for LTBI are the tuberculin skin test (TST) and two Interferon-gamma release assays (IGRAs): the QuantiFERON-TB Gold-IT (QFT-GIT) and the T-SPOT.TB®. All three lack sensitivity in PLHIV. Various strategies to discover superior LTBI screening tools are therefore being explored, including the development of IGRAs in response to alternative M. tuberculosis antigens to those used in the QFT-GIT or T-SPOT.TB®. A potential candidate is the native Heparin-Binding Haemagglutin (nHBHA), a methylated M. tuberculosis protein regarded as a latency-associated antigen. An in-house IGRA based on nHBHA (nHBHA-IGRA) has been shown to be a promising LTBI screening tool both in immunocompetent adults and in hemodialysed patients. The contribution of this nHBHA-IGRA to the detection of M. tuberculosis in PLHIV was therefore investigated. Treatment-naïve HIV-infected subjects were recruited from 4 Brussels-based hospitals. Subjects underwent screening for latent TB using the nHBHA-IGRA in parallel to the classical method consisting of medical history, chest X-ray, TST and QFT-GIT. Prospective clinical and biological follow-up ensued, with repeated testing with nHBHA-IGRA. Among 48 candidates enrolled for screening, 9 were diagnosed with LTBI by combining the TST and QFT-GIT results (3 TST+/QFT-GIT+, 1 TST+/QFT-GIT- and 5 TST-/QFT-GIT+). All 3 TST+/QFT-GIT+ patients, the TST+/QFT-GIT- patient as well an additional 3 subjects screened positive with the nHBHA-IGRA. These 3 additional patients had known M. tuberculosis exposure risks compatible with LTBI. During follow-up (median 14 months) no case of TB was reported and nHBHA-IGRA results remained globally constant. Multiplex analysis confirmed IFN- as the best read-out for the assay. From this study, we concluded that the nHBHA-IGRA appears complementary to the QFT-GIT for the screening of LTBI in PLHIV and the combination of the two tests may increase the sensitivity of screening. A large-scale study is however necessary to determine whether combining nHBHA-IGRA and QFT-GIT offers sufficient sensitivity to dismiss TST, as suggested by our results. In the same study, a group of HIV-infected adults with clinical suspicion of active TB were also recruited and tested with nHBHA-IGRA. Contrary to results in HIV-uninfected subjects, the nHBHA-IGRA could not discriminate between LTBI and active TB in PLHIV. This is an important caveat as HIV-infected subjects may present subclinical TB.A different angle was used for the third approach to the problem of LTBI in PLHIV. Systemic immune activation (SIA) is one of the principal driving forces in the natural course of HIV-infection. Despite long-term viral suppression by combination antiretroviral treatment (cART), a low-level SIA persists and is associated with an early-onset of age-associated disorders such as cardiovascular disease, dementia and osteoporosis. Causes of SIA in PLHIV are multiple and certain chronic infections appear to be implicated. A recent study in South Africa found that LTBI in PLHIV was associated with an increase in circulating activated CD8+ T-cells. If LTBI should contribute to the persistence of SIA, its screening and treatment could have an additional benefit on the clinical outcome of PLHIV. To investigate this theory, the expression of T-cell activation markers (CD38 and HLADR) as well as the level of plasmatic markers of immune activation (IL-6, sCD14, D-Dimers) were compared between subjects presenting active TB, subjects with LTBI and M. tuberculosis-free persons, with and without HIV-infection. In accordance with previous studies, active TB was associated with higher levels of SIA biomarkers in both HIV-infected and -uninfected groups. Among the HIV-uninfected subjects, no significant difference in biomarker level was found between those presenting LTBI and those with no evidence of M. tuberculosis. The effect of LTBI on activation biomarkers in the HIV-infected groups remained inconclusive because of the small number of individuals in the HIV+/LTBI group. Further investigation is therefore warranted. Interestingly, it was found that plasmatic markers may have a greater sensitivity for the detection of M. tuberculosis-associated SIA than the T-cell activation markers, an important result for future studies.Overall, LTBI in PLHIV is a challenging topic, in particular because of the lack of a gold-standard for the diagnosis of LTBI. Despite suboptimal tools, the evident clinical impact of LTBI screening and treatment in PLHIV on TB incidence justifies its implementation in standard HIV-care. In low TB-incidence countries, who, when and how to screen for LTBI in PLHIV remains unclear. This work offers an overview on the subject with particular focus on possible measures for improvement in the field.
Doctorat en Sciences médicales (Médecine)
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Roberts, Jocelyn. "Behavioural beliefs concerning gender and high-risk sexual behaviours in the context of HIV/AIDS in PNG : views from within teacher education." Thesis, Queensland University of Technology, 2012. https://eprints.qut.edu.au/54675/1/Jocelyn_Roberts_Thesis.pdf.

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Education is often viewed as a key approach to address sexual-health issues; the current concern is the burgeoning HIV/AIDS epidemic. This ethnographic study investigates the gender practices associated with high-risk sexual behaviour in Papua New Guinea as viewed by educators there. A number of practices, including gender inequality and associated sexual behaviours have been highlighted by male and female participants as escalating PNG’s HIV/AIDS epidemic. The study finds that although participants were well-informed concerning HIV/AIDS, they had varying beliefs concerning the prevailing gender/sexual issues involved in escalating highrisk behaviour and how to address the problem. The study further examines the behavioural beliefs and intentions of the educators themselves. Subsequently, within the data a number of underpinning factors, pertaining to gender, education and life experience, were found to be related to the behaviour beliefs and intentions of participants towards embracing change with regard to behaviours associated with gender equality in PNG. These factors appeared to encourage participants to adopt healthier gender and sexual behavioural intentions and, arguably, could provide the basis for ways to help address the gender inequality and high-risk behaviours associated with HIV/AIDS in PNG.

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Brookmeyer, Kathryn Amanda. "Disentangling Pathways of Adolescent Sexual Risk from Problem Behavior Syndrome." Digital Archive @ GSU, 2007. http://digitalarchive.gsu.edu/psych_diss/32.

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Understanding the development of adolescent sexual risk behavior is complicated by the co-occurrence of sexual risk with substance use and delinquency, conceptualized as “problem behavior syndrome,” with common causes and influences underlying all three problem behaviors (Jessor & Jessor, 1977). Explaining the development of sexual risk becomes even more complex given the changing patterns of adaptation and maladaptation over the course of adolescence (Sroufe & Rutter, 1984). Research also suggests that multiple pathways may forecast adolescent engagement in sexual risk behavior, underscoring the ideas of equifinality and multifinality in developmental psychopathology (Cicchetti & Rogosh, 1996). To understand the diverse nature of sexual risk taking, researchers must identify these pathways and disentangle co-occurring problem behaviors from sexual risk. Revealing the course of sexual risk taking and the early risk and protective processes through which problem behavior develops allows researchers to identify the developmental periods that would be most amenable to intervention efforts (Rolf et al., 1990). Using data from the National Longitudinal Survey of Youth (NLSY79), this study aimed to disentangle problem behavior syndrome by identifying the unique developmental pathways of adolescent sexual risk, alcohol use and delinquency. This study also investigated how early adolescent processes of risk and protection were associated with the growth of these risk behaviors during adolescence. Using a developmental psychopathology and resilience framework, risk trajectories were measured with adolescents aged 15 to 24, and antecedents were measured with early adolescents ages 10 to 14 (N= 1778). Using Latent Class Growth Analyses (LCGA), joint trajectory analyses revealed five distinct adolescent risk taking groups: high sex and alcohol, moderate problem behavior, problem behavior, alcohol-only, and alcohol and delinquency experimentation. Early adolescent externalizing problems were particularly important in understanding adolescent risk group membership. The co-occurrence between sexual risk and alcohol use, the diversity of problem behavior syndrome, and potential intervention and prevention efforts are discussed.

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Jaafoura, Salma. "Mémoire lymphocytaire T et persistance virale." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114847.

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Au cours d’une réponse immunitaire primaire, les lymphocytes T CD8 mémoires émergent à partir d'un environnement de forte activation immunitaire. Les cellules régulatrices T CD4 FoxP3+ (LTregs) jouent un rôle clé de suppression de la réponse immunitaire. Nous montrons que les LTregs sont nécessaires pour la génération d’une réponse mémoire T CD8 fonctionnelle. En absence de LTregs lors du priming, les LT CD8 mémoires générées prolifèrent faiblement et ne parviennent pas à se différencier après une réactivation antigénique en effecteurs cytotoxiques secondaires fonctionnelles. Nous suggérons que les LTregs agissent tôt, lors de la phase d'expansion des LT CD8, en réduisant l’exposition des précurseurs mémoires T CD8 à l'interleukine-2. Ce nouveau rôle crucial des LTregs a des implications pour le développement optimal de vaccin.Chez les patients sous traitement antirétroviral efficace et prolongée (ART), le VIH peut persister dans un petit pool de cellules T CD4 mémoires quiescentes de longue durée de vie infectées par du virus latent intégré. Ce réservoir latent comprend différentes sous-populations mémoires. Nos résultats suggèrent une contraction progressive de la taille du réservoir latent autour d'un noyau formé de sous-populations T CD4 mémoires moins différenciées (centrales mémoires TCM et souches mémoires TSCM). Ce processus très lent semble dépendre de la taille initiale et du taux de décroissance qui diffère entre les sous-populations mémoires infectées de manière latente. Nos résultats suggèrent également une extrême stabilité du sous-réservoir TSCM, dont la taille est directement liée à l'exposition cumulée au virus plasmatique avant le début du traitement ART, soulignant l'importance d'une initiation précoce du traitement antirétroviral efficace. La présence de cette dynamique intrinsèque dans le réservoir latent peut avoir des implications pour la conception de stratégies optimales de purge thérapeutique contre le VIH
During the primary immune response, CD8 memory emerges from an environment of strong immune activation. The FoxP3 regulatory CD4 T-cell subset (Treg) is known as a key suppressive component of the immune system. We report that Tregs are required for the generation of functional CD8 memory. In the absence of Tregs during priming, the resulting memory cells proliferate poorly and fail to differentiate into functional cytotoxic secondary effectors following antigen reactivation. We find that the Tregs act early, during the expansion phase of primary CD8 effectors, by fine tuning interleukin-2 exposure of CD8 memory precursors. This crucial new role of Tregs has implications for optimal vaccine development. In patients who are receiving prolonged antiretroviral treatment (ART), HIV can persist within a small pool of long-lived resting memory CD4 T cells infected with integrated latent virus. This latent reservoir involves distinct memory subsets. We provide results that suggest a progressive reduction of the size of the blood latent reservoir around a core of less-differentiated memory subsets (central memory and stem cell-like memory).This process appears to be driven by the differences in initial sizes and decay rates between latently infected memory subsets. Our results also suggest an extreme stability of the TSCM sub-reservoir, the size of which is directly related to cumulative plasma virus exposure before the onset of ART, stressing the importance of early initiation of effective ART. The presence of these intrinsic dynamics within the latent reservoir may have implications for the design of optimal HIV therapeutic purging strategies

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Vasconcelos, Ludmila Moreira. "Tratamento de tuberculose latente: um desafio para o controle da doença." Faculdade de Medicina de São José do Rio Preto, 2017. http://hdl.handle.net/tede/441.

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early detection of latent tuberculosis infection is one of the TB control strategy recommended by the World Health Organization. Objective: to analyze the association of latent tuberculosis infection with sociodemographic, clinical and risk factors for active TB cases chemoprophylaxis. Material and Methods: A retrospective cross-sectional epidemiological study, based on secondary data chemoprophylaxis notification form of tuberculosis of the state information system (TBWEB) of Epidemiological Surveillance Group XXIX (GVE 29) of São José do Rio Preto. They considered all reported cases from 2009 to 2013. The selected variables were sociodemographic and clinical. For the analysis, all statistical tests were applied with a 0.05 significance level. The software used for analysis were Minitab® 17 (Minitab Inc.) and Statistica 10 (StatSoft Inc.). Results: predominance of females, mean age 37.51 years and median of 40.00 years. Smear the day with negative sputum was associated significantly with cough (P = 0.001) and occupation (P <0.001). Few HIV / AIDS and health care professionals made the smear and sputum culture. Conclusion: The study found it hard both in screening latent tuberculosis, as in diagnosis and treatment, which may contribute to the spread of TB and multidrug resistance, increasing the morbidity and mortality rates from the disease, particularly among co-infected with HIV.
a detecção precoce da tuberculose infecção latente é uma das estratégias de controle da tuberculose recomendada pela Organização Mundial de Saúde. Objetivo: analisar a associação da tuberculose de infecção latente com variáveis sociodemográficas, clínicas e fatores de risco para tuberculose ativa de casos de quimioprofilaxia. Material e Método: estudo epidemiológico transversal retrospectivo, a partir de dados secundários da ficha de notificação de quimioprofilaxia da tuberculose do sistema de informação estadual (TBWEB) do Grupo de Vigilância Epidemiológica XXIX (GVE 29) de São José do Rio Preto. Foram considerados todos os casos notificados de 2009 a 2013. As variáveis selecionadas foram as sociodemográficas e clínicas. Para a análise, todos os testes estatísticos foram aplicados com nível de significância de 0,05. Os softwares utilizados para análise foram o Minitab® 17 (Minitab Inc.) e Statistica 10 (StatSoft Inc.). Resultados: predomínio do sexo feminino, idade média 37,51 anos e mediana de 40,00 anos. Realização da baciloscopia com resultado negativo do escarro se associou de forma significativa com a tosse (P=0,001) e ocupação (P<0,001). Poucos portadores de HIV/Aids e profissionais de saúde realizaram a baciloscopia e cultura do escarro. Conclusão: O estudo mostrou dificuldades tanto no rastreio de tuberculose infecção latente, como no diagnóstico e tratamento, o que pode contribuir para a multirresistência e disseminação da TB, aumentando as taxas de morbimortalidade pela doença, principalmente entre os coinfectados pelo HIV.

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23

Dahabieh, Matthew Solomon. "Regulation of HIV-1 latency by basal transcription." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44153.

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24

Santos, Danielle Talita dos. "Prova tuberculínica e infecção latente das tuberculose entre indivíduos com HIV/AIDS." Universidade Estadual de Londrina. Centro de Ciências da Saúde. Programa de Pós-Graduação em Enfermagem, 2013. http://www.bibliotecadigital.uel.br/document/?code=vtls000188990.

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A tuberculose é uma importante causa de mortalidade entre indivíduos com HIV/aids. A Prova Tuberculínica (PT) é um exame utilizado como recurso diagnóstico que identifica a Infecção Latente da Tuberculose (ILTB) e, dessa forma, permite o tratamento profilático. Pessoas com HIV/aids fazem parte dos grupos que estão sob a recomendação da realização periódica da PT e tratamento da ILTB com a finalidade de evitar seu adoecimento. O objetivo deste estudo foi analisar a frequência de realização das PT nos indivíduos portadores de HIV/aids, assim como a prevalência e a evolução dos casos de infecção latente da tuberculose. Estudo do coorte retrospectivo, com abordagem quantitativa, realizado no Centro de Referencia pata tuberculose e aids (CR) da cidade de Londrina-PR. A população de estudo foi composta por 880 pacientes que realizaram a PT entre 2003 e 2010 com registro no Livro de PT do Ambulatório de Pneumologia. Os dados foram completados utilizando-se os prontuários dos pacientes e as fichas do Sistema de Informações de Agravos de Notificação, notificados até dezembro de 2012. Os dados foram tabulados no programa SPSS 20.0 e para análise estatística foram aplicados teste t nas variáveis com distribuição normal e teste Mann- Whitney naquelas sem distribuição normal. Para verificar associação entre variáveis utilizou-se os testes qui-quadrado e exato de Fisher e nível de significância de 5%. Houve uma perda de 113 prontuários e a amostra foi constituída por 767 pacientes, dos quais 69 (9,0%) nunca realizaram a leitura da PT. Dentre os 698 casos que completaram a PT, a positividade foi de 9,5%. Foram realizados 1172 exames na população de estudo, resultando em uma média de 1,52 PT solicitada e 1,32 PT realizada (com leitura) por paciente, frente a uma média de tempo de acompanhamento no CR de 7,7 anos. Observou-se associação com significância estatística entre a positividade à PT e o sexo masculino, o mesmo ocorrendo com moradia/presídio, tendo em vista que 41,7% dos encarcerados apresentaram PT com resultado reator. Dentre os 66 casos com PT positiva, 53 (80,3%) caracterizavam-se como ILTB, portanto, com indicação de tratamento, dos quais 39 (73,6%) iniciaram o tratamento e 10 (25,6%) abandonaram o tratamento. Observou-se associação com significância estatística entre contagem maior de CD4+ (>201 cel/mm3) e reatividade a PT. Identificaram-se 58 (7,5%) casos de Tuberculose, entre estes, 22,4% abandonaram o tratamento. Com relação aos 21 casos de óbitos 9,5% estiveram associados a TB. A adesão à realização da PT e tratamento da ILTB tem sido de difícil emprego. Devem-se reforçar políticas de saúde voltadas para fortalecer acesso e seguimento dos pacientes com concomitante capacitação e sensibilização de profissionais, visando aumentar o uso da PT nos indivíduos com HIV/AIDS. O abandono do tratamento da ILTB e TB nos casos indicados foi considerável; situação que reforça a necessidade de ações de supervisão e controle dos pacientes que necessitam desta terapia visando a melhoria da saúde destes indivíduos.
Tuberculosis is an important cause of mortality among individuals with HIV/AIDS. Tuberculin skin test (TST) is a test used as a diagnostic tool that identifies the Latent Tuberculosis Infection (LTBI) and thus allows prophylactic treatment. People with HIV/AIDS are part of groups that are under the recommendation of periodical PT and treatment of LTBI in order to prevent their illness. The aim of this study was to analyze the frequency of application of the tuberculin test in individuals with HIV / AIDS , as well as the prevalence and outcome of cases of latent TB infection . Retrospective cohort study with a quantitative approach, performed in the Reference Center paw tuberculosis and AIDS (RC) in the city of Londrina-PR. The study population consisted of 880 patients who underwent TST between 2003 and 2010 with registration in the Book of the PT Clinic of Pulmonology. The data were completed using patient charts and records of the Information System for Notifiable Diseases, reported through December 2012. Data were tabulated using SPSS 20.0 program for statistical analysis and t test in normally distributed variables and Mann-Whitney test those without normal distribution. To assess the association between variables we used the chi-square and Fisher's exact test and a significance level of 5%. A loss of 113 records and sample comprised 767 patients, of whom 69 (9.0 %) never had read the TBST. Among the 698 cases who completed the TBST, the positivity was 9.5 %. 1172 examinations were performed in the study population, resulting in an average of 1.52 TBST requested and 1.32 TBST held (with reading) per patient, compared with an average follow-up time of 7.7 years in RC. We observed statistically significant association between a positive TBST and male, the same occurring with housing / prison , considering that 41.7 % of prisoners had TST results reactor. Among the 66 cases with positive TBST, 53 (80.3 %) were characterized as LTBI, thus indicating treatment, of whom 39 (73.6 %) started treatment and 10 (25.6 %) left the treatment. We observed statistically significant association between higher CD4 + counts (> 201 cells/mm3) and reactivity to TBST. We identified 58 (7.5 %) cases of tuberculosis, among these, 22.4 % abandoned treatment. Regarding the 21 cases of deaths 9.5% were associated with TB. Adherence to the realization of TBST and treatment of LTBI has been difficult job. Should strengthen health policies aimed at strengthening access to and monitoring of patients with concomitant sensitization and training of professionals, to increase the use of TBST in individuals with HIV / AIDS. Noncompliance with treatment of LTBI and TB as indicated was handsome; situation reinforces the need for further supervision and control of patients requiring this therapy aimed at improving the health of these individuals.

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Friedman, Julia H. "HIV-1 Latency as a Consequence of Chromatin Regulation." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1301495389.

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Tong, Phuoc Bao Viet. "Développement d’une nouvelle classe d'agents de sortie de latence du VIH-1." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT009.

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Bien que le traitement antirétroviral (ART) supprime efficacement la multiplication du VIH-1 chez les patients infectés, l’ART ne guérit pas l'infection. En effet, si l'ART est arrêté, on observe un rebond viral. Celui-ci est principalement dû à l'activation stochastique de cellules latentes qui contiennent le génome viral intégré mais ne produisent pas de virus et ne sont donc pas ciblées par l'ART ou le système immunitaire. Ces cellules latentes sont peu nombreuses (1-10 par million de cellules T-CD4+ quiescentes) mais elles apparaissent rapidement après la primo infection (en quelques jours), ont une longue durée de vie (près de 4 ans de demi-vie). Ces cellules réservoirs constituent donc un obstacle majeur à l'éradication virale.La stratégie la plus prometteuse pour supprimer ces cellules, dite "Shock and Kill", (ou "kick and kill" est de les activer pour qu'elles soient ensuite détruites par la production virale, ciblées par l'ART et/ou lysées par les cellules T cytotoxiques. Un certain nombre d’agents de sortie de latence (LRAs) ont été développés pour activer ces cellules. Ils ciblent des protéines cellulaires telles que les histone-désacétylases (HDAC) ou la protéine kinase C. La plupart d'entre eux présentent donc des effets non spécifiques, comme l'inhibition des lymphocytes cytotoxiques, et parfois une toxicité. Ils ont été incapables de diminuer la taille du réservoir chez les patients VIH+.Nous avons développé une nouvelle famille d’agents de levée de latence du VIH ciblant une protéine virale. Sur la base des structures disponibles, nous avons identifié par criblage in silico des ligands potentiels de cette protéine. Dix molécules ont été sélectionnées. Aucune n'est toxique pour les cellules T CD4+. Une molécule appelée D10 se fixe spécifiquement à la cible avec une affinité de l’ordre de 30 -50 nM et affecte l'activité biologique de cette protéine. De plus, D10 présente une activité LRA sur les lignées cellulaires latentes JLat-9.2 et OM-10.1. L’activité LRA de D10 sur ces lignées représente 50 à 70% de celle du SAHA (vorinostat), un inhibiteur des HDAC candidat LRA en cours d’essais cliniques (Phase 2). Lors de tests ex vivo sur les cellules latentes de patients VIH traités, D10 à 50 nM a une activité LRA très efficace, 80% supérieure à celle de la bryostatine-1 qui agit sur la PKC et est considéré comme le LRA le plus prometteur actuellement. En utilisant une approche chémoinformatique nous avons sélectionné 11 analogues de D10, dit N1-N11. Certains de ces analogues (N5, N8) montrent un effet plus fort que D10 sur les lignées cellulaires latentes. L'étude de cette famille nous a permis d'ébaucher une relation structure chimique / activité LRA de ces molécules. Nous avons donc identifié de nouveaux agents de sortie de latence du VIH-1 qui ciblent une protéine virale et devraient donc être plus spécifiques que les LRAs ciblant les protéines cellulaires
Despite its efficiency to prevent viral multiplication, antiretroviral therapy (ART) is unable to cure patients with HIV-1. Indeed, if ART is stopped, a viral rebound is observed. This increase in blood viral load is due to the activation of HIV-1 reservoirs, among which latently-infected memory CD4+ T cells. These cells are rare (1-10 per million of quiescent T cells), appear very quickly following infection and have a long half-life (almost 4 years). To purge this long-lived reservoir the "Shock and Kill" (or kick and kill) approach was developed. This strategy relies on the use of latency reversing agents (LRAs) to induce reservoir activation. All LRAs developed until now target cellular proteins such as histone deacetylases or protein kinase C. These LRAs did not affect the reservoir size of HIV+ patients.Here we present a new LRA family that binds to and activates an HIV-1 protein. These compounds were identified by in silico screening, are not cytotoxic and affect the biological activity of their target. They were less efficient than available LRAs on HIV-1 latent cell lines. Nevertheless, when tested on latent T-cells from HIV-1 patients in ex vivo assays, the lead compound D10 at 50 nM was ~ 80% more efficient than bryostatin-1, one of the best LRA available to date.Using a chemoinformatic approach, we selected 11 analogs of D10, termed N1 to N11. Some of these analogs (N5, N8) showed a stronger effect than D10 on latent cell lines. The study of this family enabled us to elaborate a structure/ function relationship.We thus identified a new family of HIV latency reversing agents targeting a viral protein and that should therefore be more specific than LRAs that target cellular proteins

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Lam, Cindy. "Effects of APOBEC3-Induced Mutations on HIV-1 Expression and Latency." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39811.

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One of the greatest barriers to curing HIV-1 is the ability of the virus to establish a state of latent infection within infected cells. During viral latency, the virus lies dormant in the form of an integrated, replication-competent provirus within the infected cell. In this state, the virus is undetectable by the host immune system and is unaffected by antiretroviral drugs due to extremely weak or null transcription. These viruses, however, can be induced to produce infectious virus later on and propagate the infection as well as reseed the latent reservoir. The factors that lead to the establishment and maintenance of HIV-1 latency are not all known. Current latency reversal methods are unable to effectively purge the latent reservoir in HIV-1-infected patients, which begs the question whether there are populations of latently-infected cells that are not being targeted by present therapeutics. One of our first lines of defense against retroviral infection is the APOBEC3 family of cytidine deaminases. These enzymes restrict retroviral infection mainly through hypermutation of the proviral DNA, leading to inactivation of the virus. However, it has been shown that low levels of mutations do not necessarily inactivate the virus and can sometimes be beneficial for the virus by increasing genetic diversity and viral fitness. Sublethal mutagenesis has been studied on coding regions of the virus, however, their effects on regulatory regions of the virus such as the LTR promoter have been scarcely explored. My project aimed to examine the effects of APOBEC3-induced mutations on the activity of the HIV-1 LTR promoter and investigate whether these mutations could be generating a subset of latently-infected cells. A library of HIV-1 clones with A3G- or A3F-mutated LTRs was generated. We discovered that the 5’ LTR is not mutated during the first round of HIV-1 infection in our system while the 3’ LTR accumulates mutations. A second round of infection is required for the mutations in the 3’ LTR to be copied over to the 5’ LTR and influence promoter activity. The mutations generated a range of effects on the promoter, with some clones being completely inactivated and no longer responsive to Tat or PMA/Ionomycin induction, while other clones were still highly infectious. The clones of interest were the ones in between this spectrum that were weakly-infectious (≤0.25%) prior to stimulation but were able to be induced above a given threshold (≥10-fold). We denoted these clones latency-prone viruses (LPVs) and were able to identify 10 of these clones within our library. We also explored the effects of individual mutations on the promoter and although these clones were highly infectious, we identified 8 positions of interest that led to weaker infectivity and fluorescence when mutated. The mutations in our library were found to hit important transcription factor binding sites and were also identified in a bioinformatics search of HIV-1-infected patient sequences, which confirms the relevance of our in vitro-identified mutations in a physiological setting. This is the first investigation and evidence of the APOBEC3 proteins contributing to the generation of a subset of latent viruses and constitutes an important contribution to the understanding of HIV-1 latency and its reversal. This previously uncharacterized pool of latently-infected cells could explain why current therapies are ineffective as they do not target these molecular modifications but rather focus on reversing epigenetics and reactivation of the virus. These newly-discovered latency-prone viruses would be a useful tool in testing reactivation drugs and establishes the need to develop novel antiretrovirals that will target a broader spectrum of latently-infected cells. This project has effectively illustrated the dual role of this host-encoded restriction factor and provided further insight into HIV-1 latency, the major hurdle towards a cure for HIV-1.

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Souza, Josiane Maria Oliveira de. "Prova tuberculínica e QuantiFERON-TB Gold in-Tube na identificação da infecção latente pelo Mycobacterium tuberculosis em pessoas vivendo com AIDS." reponame:Repositório Institucional da UnB, 2014. http://repositorio.unb.br/handle/10482/17390.

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Tese (doutorado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Departamento de Enfermagem, Programa de Pós-Graduação em Enfermagem, 2014.
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A tuberculose (TB) é a mais freqüente e fatal doença oportunista em pessoas vivendo com HIV/aids (PVHA), em função do maior risco de seu desenvolvimento após a infecção pelo Mycobacterium tuberculosis. O diagnóstico e tratamento da infecção latente pelo Mycobacterium tuberculosis (ILTB) na PVHA é fundamental para evitar a progressão para doença e morte por TB. O presente estudo tem por objetivo analisar o uso dos testes Prova Tuberculínica (PT) e QuantiFERON-TB Gold in-Tube (QTF-GIT) na identificação da ILTB em pessoas vivendo com aids. A pesquisa utilizou os modelos epidemiológicos do tipo transversal, série de casos e estudo de caso. A amostra consistiu de 300 pacientes com HIV/aids, selecionados em oito serviços de assistência especializados em DST/HIV/aids do Distrito Federal, entre 2011 e 2013, com seguimento até maio de 2014. A análise dos dados transversais revelou uma média de CD4 de 477,5células/mm³, sendo que 18 pacientes (6%, IC95%:3,6-9,3) apresentaram ILTB a partir do resultado positivo da PT e/ou QTF-GIT. Destaca-se que quatro pacientes (1,3%, IC95%:0,04-2,63) apresentaram uma PT positiva e oito pacientes (2,7%, IC95%:0,8-4,5) apontaram para o teste QFT-GIT positivo, sendo que seis pacientes (2%, IC95%:0,4-3,6) obtiveram resultados positivos para ambos os testes – aumento de 81,8% na detecção de ILTB pelo QFT-GIT em relação à PT. A concordância entre os dois testes foi de 96% (kappa=0,48). Do total de casos, 295 pacientes (98,3%) utilizavam terapia antirretroviral. No seguimento, dezessete pacientes foram identificados com ILTB (5,1%), sendo que doze casos (70,6%) realizaram a terapia preventiva com isoniazida (TPI) – nenhum destes adoeceu por TB. A média de proteção após a TPI foi de 495,4 dias para QTF-GIT+ e de 540 dias, a PT≥5mm. Os resultados revelaram baixa prevalência de ILTB a partir dos resultados da PT e QTF-GIT na referida população em cenário de baixa carga da TB e média renda, o que limitou a capacidade de avaliar os fatores preditores associados aos resultados positivos dos testes. Na população com imunossupressão moderada houve melhor resposta ao QTF-GIT do que a PT, para detecção da ILTB. No seguimento dos casos identificaram-se dois casos de TB pulmonar entre os pacientes com resultado negativo do QTF-GIT e PT, com atipia na apresentação clínica e laboratorial, além de boas condições socioeconômicas e moderada contagem de CD4, o que demonstrou que mesmo com uso adicional de um teste, não foi possível identificar e tratar todos os pacientes com risco de desenvolvimento da TB entre as PVHA. O único óbito ocorrido no estudo não foi relacionado à TB. Concluiu-se que é preciso a execução de demais estudos que avaliem outros fatores de risco e biomarcadores para ILTB entre as PVHA, mesmo diante dos resultados negativos, além da necessidade de maior tempo de seguimento para avaliar a durabilidade da proteção pela isoniazida e de estudos que explorem a relação custoefetividade do uso do QTF-GIT entre as PVHA. _________________________________________________________________________________ ABSTRACT
Tuberculosis (TB) is the most frequent and fatal opportunistic infection in people living with HIV/AIDS (PLWHA), due to the higher risk of developing TB after infection with Mycobacterium Tuberculosis. Hence, the diagnosis and treatment of latent Mycobacterium Tuberculosis infection (LTBI) in PLWHA is essential to prevent disease progression and death from TB. The study aims to analyze the use of two tests Tuberculin skin testing (TST) and QuantiFERON-TB Gold In-Tube (QTF-GIT) in the identification of LTBI in people living with AIDS. Used the cross-sectional epidemiological models, case series and case study. The sample consisted of 300 patients with HIV/AIDS of the Federal District, between 2011 and 2013, with follow-up through May 2014 the analysis of cross-sectional data revealed in the average CD4 count of 477.5 cells/mm ³ and 18 patients (6%, 95% CI: 3.6-9.3) had LTBI positive result from the TST and/or QTF-GIT. Four patients (1.3%, 95% CI: 0.042.63) had a positive TST-eight (2.7%, 95% CI: 0.8-4.5) tested positive QFT-GIT, and six (2%, 95% CI 0.4-3.6) had positive results for both tests. That is, a relative increase of 81.8% in detecting LTBI by QTF-GIT compared to the TST. The agreement between the two tests was 96% (kappa =0.48). Of the total cases, 295 patients (98.3%) were using antiretroviral therapy. Following seventeen patients were identified with LTBI (5.1%), while 12 cases (70.6%) underwent isoniazid preventive therapy (IPT), and among them, none became ill with TB. The average protection after IPT was 495.4 days for QTF-GIT + and 540 days, TST≥5mm. The results showed a low tuberculosis burden and middle income, which limited the ability to assess the predictive factors associated with positive test results scenario. Individuals with moderate immunosuppressant responded better to QTF-GIT than the TST, to detect LTBI. Following the cases, there were limitations in identifying all patients susceptible to developing TB. During follow-up there were two cases of Pulmonary tuberculosis among patients with negative results of QTF-GIT and TST, with atypical in clinical and laboratory presentation, but good socioeconomic conditions and moderate CD4 count. What has shown that even with the additional use of a diagnostic test was not possible to identify and promptly treat all patients with HIV/AIDS at risk of developing TB. The only death in the study was not related to tuberculosis. Finally, we suggest further studies that assess other risk factors and biomarkers for LTBI among PLWHA, despite the negative results. Besides being required longer follow-up to evaluate the durability of protection by isoniazid and studies exploring the cost-effectiveness of using QTF-GIT among PLWHA relationship. _________________________________________________________________________________ RESUMEN
La tuberculosis (TB) es la enfermedad oportunista más frecuente y fatal en personas que viven con VIH/sida (PVVS), en función del mayor riesgo de desarrollar TB después de infección por Mycobacterium tuberculosis. Por consiguiente, el diagnóstico y tratamiento de la infección latente por Mycobacterium tuberculosis (ILTB) en las PVVS es fundamental para evitar la progresión a enfermedad y muerte por TB. El objetivo de este estudio es analizar el uso de dos pruebas, la Prueba Tuberculínica (PT) y QuantiFERON-TB Gold in-Tube (QTFGIT) en la identificación de la ILTB en personas que viven con el sida. Se utilizaran los modelos epidemiológicos de tipo transversal, serie de casos y estudio de caso. La muestra consistió en 300 pacientes con VIH/sida, seleccionados en ocho servicios especializados en ETS/VIH/sida del DF, entre 2011 y 2013, con seguimiento hasta mayo de 2014. El análisis de los datos transversales reveló un promedio de CD4 de 477,5 células/mm³ y 18 pacientes (6%, IC95%:3,6-9,3) tuvieran ILTB a partir del resultado positivo de la PT y/o QTF-GIT. Cuatro pacientes (1,3%, IC95%:0,04-2,63) presentaron una PT positiva y ocho (2,7%, IC95%:0,8- 4,5) la prueba QFT-GIT positiva y seis (2%, IC95%:0,4-3,6) tuvieron resultados positivos en las dos pruebas. Es decir, un incremento relativo de 81,8% en la detección de ILTB por el QFT-GIT en relación con la PT. La concordancia entre las dos pruebas fue de 96% (kappa=0,48). Del total de casos, 295 pacientes (98,3%) utilizaban terapia antirretroviral. Siguiente diecisiete pacientes fueran identificados con ILTB (5.1%) y 12 de estos casos (70.6%) se sometieron a la terapia preventiva con isoniazida (TPI), y, entre ellos, ninguno se enfermó de TB. La media de protección después de la TPI fue de 495,4 días para QTF-GIT+ y de 540 días, la PT≥5mm. Los resultados mostraron una baja prevalencia de ILTB a partir de los resultados de la PT y QTF-GIT en esa población en escenario de baja carga de tuberculosis y media renta, lo que limitó la capacidad de evaluar los factores predictores asociados a los resultados positivos de las dos pruebas. Los casos con inmunosupresión moderada respondieron mejor al QTF-GIT que a la PT, para detectar la ILTB. En el seguimiento de los casos, hubo limitación en la identificación de todos los pacientes susceptibles a desarrollar TB. Durante el seguimiento hubo dos casos de tuberculosis pulmonar entre los pacientes con resultado negativo del QTF-GIT y PT, con atipia en la presentación clínica y de laboratorio, además de buenas condiciones socioeconómicas y 13 moderado recuento de CD4. Lo que demostró que a pesar del uso adicional de una prueba diagnóstica no fue posible identificar y tratar tempranamente a todos los pacientes con VIH/sida en riesgo de desarrollar TB. La única muerte ocurrida en el estudio no estaba relacionada con la tuberculosis. Por último, se sugiere más estudios que evalúen otros factores de riesgo y biomarcadores para ILTB entre las PVVS, a pesar de los resultados negativos. Además de la necesidad de un mayor tiempo de seguimiento para evaluar la durabilidad de la protección por la isoniazida y de estudios que exploren la relación costo-efectividad del uso del QTF-GIT entre las PVVS.

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Smutná, Katarína 1991. "Schlafen 12, a novel HIV restriction factor involved in latency." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/666297.

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The process of HIV latency establishment and maintenance is not clearly understood. Homeostatic proliferation (HSP) is a major mechanism by which long-lived naive and memory CD4 T cells are maintained in vivo. HSP also contributes to the persistence of HIV latent reservoir. Furthermore, HIV-infected naive CD4 T cells cultured under HSP condition are refractory to reactivation, in contrast to TCR-activated memory CD4 T cells. This might be due to the suggested post-transcriptional block in naive HSP-cultured cells. Here we compared a transcriptomic signature of naive and memory CD4 T cells. Among differentially expressed genes that may influence HIV latency, we identified Schlafen 12 (SLFN12) as an interesting candidate for a potential HIV restriction factor. Our results showed that SLFN12 establishes post-transcriptional block in HIV infected cells and thus inhibits both, HIV production as well as its reactivation from latently infected cells. These findings may help to better understand the mechanisms underlying HIV latency and its reversal in HSP-maintained naive CD4 T cells. All together it might contribute to the design of novel HIV eradication strategies.
El proceso por el cual el virus de la Inmunodeficiencia Humana (VIH) establece y mantiene un estado de latencia no se conoce en su totalidad. La proliferación homeostática (HSP, de sus siglas en ingés “Homeostatic proliferation”) es uno de los mecanismos por el cual las células T CD4 “naive” y de memoria se mantienen in vivo. Además, HSP también contribuye al mantenimiento del reservorio de virus en forma latente. Además, las células T CD4 “naive” infectadas y cultivadas en condiciones de HSP no son capaces de reactivarse a diferencia de las células T CD4 de memoria activadas vía TCR. Estudios previos sugieren que esta observación se debe a un bloqueo post-transcripcional en células T “naive” cultivadas en condiciones de HSP. En esta tesis comparamos la perfil del transcriptoma de células T CD4 “naive” y de memoria. Entre los genes diferencialmente expresados que podrían participar en el proceso de latencia del VIH, identificamos Schlafen 12 (SLFN12) como un candidato interesante que podría ser un factor de restricción del virus. Los resultados de este trabajo muestran que SLFN12 establece un bloqueo post-transcripcional en células infectadas por VIH, y de esta forma inhibe tanto la producción del virus como su reactivación en células infectadas de forma latente. Estas observaciones pueden ser de gran ayuda para entender mejor los mecanismos subyacentes a la latencia del VIH así como su reactivación en células CD4 T “naive” mantenidas bajo condiciones de HSP. En su conjunto, estos resultados podrían contribuir al diseño de nuevas estrategias para erradicar el VIH.

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Al, Ali Sally. "NOVEL APPROACHES FOR THE ERADICATION OF HIV LATENTLY INFECTED CELLS." Wright State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=wright1377374244.

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31

Rodriguez, Ailin. "Cross-sectional Predictors of HIV Risk among Latino Migrant Workers." FIU Digital Commons, 2018. https://digitalcommons.fiu.edu/etd/3711.

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The relationship between suspected predictors of current HIV risk, i.e. self-efficacy, social norms, expectancies, alcohol use, past HIV risk, past history sexual abuse, social support, and behavioral intention was investigated in a sample of Latino migrant workers living and working in the United States (N=270) using baseline data from a previous study. A series of multiple regression analyses were performed by adjusting for socio-demographic characteristics such as age, gender, marital status, educational attainment, and length of stay. Zero-inflated Poisson regression analysis showed that self-efficacy was associated with behavioral intention (β= 0.03, p= 0.04) and expectancies was associated with behavioral intention (β= -0.01, p = 0.04). Binary logistic regression analysis showed that past HIV risk was associated with the dependent variable, current HIV risk (β = 0.11, p= 0.01), while behavioral intention was associated with current HIV risk (β= -0.16, p= 0.02). Bayesian path analyses showed behavioral intention to partially mediate the relationship between self-efficacy and current HIV risk (β= 0.24, 95% CI: 0.10, 0.38) and to fully mediate the relationship between AOD use and HIV risk (β= 0.11, 95% CI: -0.05, 0.26). In summary, two socio-psychological factors emerged as significant predictors of HIV risk. Lower levels of behavioral intention and higher levels of past HIV risk were associated with higher current HIV risk. These findings are relevant for informing future studies on Latino migrant workers or similar populations and for planning interventions designed to prevent and/or reduce HIV risk.

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32

Greig, Matthew. "Characterization of HIV-1 Proviral Latency Induced Through APOBEC3 Mutagenesis and Reverse Transcriptase Error." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/41078.

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Human Immunodeficiency Virus 1 (HIV-1) is a lentivirus that forms persistent latently infected reservoirs that are the remaining major hurdle for current HIV-1 treatments. APOBEC3 (A3) proteins are intrinsic retroviral restriction factors that introduce GA mutations during reverse transcription, while Reverse Transcriptase (RT) introduces on average 2-3 mutations every reverse transcription cycle due to a lack of proofreading ability. The goal of this research is to characterize the infectivity and activation of mutated HIV-1 viruses that display reduced transcription upon infection, viruses that we term latency prone viruses (LPVs). We hypothesize that GA transition mutations in the HIV-1 Long Terminal Repeat (LTR) region of the LPVs introduced through Reverse Transcriptase and low levels of A3 protein activity can create HIV-1 sequences that display a reversible, latency-like phenotype. Variable levels of transcription and promoter activation were seen among the LPVs when tested against four classes of Latency Reversing Agents (LRAs). Subsequently, three tested LPVs demonstrated an initial latency-like phenotype before rebounding in infectivity. This project demonstrates for the first time that HIV-1 latency is not simply a byproduct of the infection timing and cellular conditions, but that replication-competent HIV-1 latent viruses can also be created through sublethal mutagenesis of their viral promoter sequence introduced through A3 and RT exposure. The characterization of the complete mechanism of HIV-1 latency induction, maintenance, and reversal is critical in the development of sterilizing and functional cures for HIV-1 infection.

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33

Nonodi, Thato Pearl. "NMR Metabonomics in an in vitro Model of HIV-1 latency." Diss., University of Pretoria, 2017. http://hdl.handle.net/2263/63280.

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Background: Metabolic disorders have been identified in patients infected with the human immunodeficiency virus (HIV). These disorders include lipodystrophy, wasting syndrome, cardiovascular disease and glucose intolerance. Highly active antiretroviral treatment (HAART) administered to patients can successfully suppress the virus and decrease the prevalence of opportunistic infections associated with AIDS but increase incidence of metabolic disorders. Glucose tolerance test, dual-energy x-ray absorptiometry and CD4 counts are some of the conventional tests that are used to detect and monitor disease progression and metabolic disorders. These are single result tests that are time-consuming and provide limited information about the metabolic disorder. A metabonomic approach allows for the measurement of multiple metabolites simultaneously; which could lead to the identification of markers of disease progression. Most HIVmetabonomics studies to date used nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) spectrometry to detect multiple metabolites from blood and urine samples simultaneously, fewer studies utilized cell culture supernatants as metabolite source. In the body HIV is able to seize control of cellular networks and exists as an active or latent virus. HIV latency is mainly responsible for survival of the virus through the production of reservoirs throughout the body. It is then of great interest to investigate the effects of active and latent virus on cell metabolic networks. In vitro cell models such as U1 cells, a promonocyte latently infected with HIV-1 are suitable for such investigations because the models allow for control over activation of the virus with stimulants. To date only one study has compared the metabolic profiles of the active virus against non-infected cells but no study has comparatively investigated actively and latently infected immune system U1 cells, which is what is presented here. In this study a metabonomic approach was used to investigate active and latently infected U1 promonocytic cells and the metabolites were detected by NMR spectroscopy. Methods: U1 and U937 cells were cultured and lysed by the freeze-thaw method to extract the supernatant, the extent of cell lysis was determined through flow cytometry. NMR spectroscopy was used to detect metabolic profiles of uninfected U937 cells (parent cell line from which U1 cells were derived) as well as actively and latently infected U1 cells. Phorbol myristate acetate (PMA) was used as a stimulant to activate the virus. NMR data was preprocessed for statistical analysis with Mestrenova 10.0 software, and the metabolites were putatively identified with the use of Chenomx software, literature searches, human metabolome database (HMDB) and Kyoto encyclopedia of genes and genomes (KEGG). For statistical data analysis SPSS 20.0 software was used to determine group separation and metabolic profile differences. Results: Glucose, lactate, glutamine/glutamate, leucine, alanine, choline, phosphocreatine and lipid are some of the metabolites that were detected by NMR spectroscopy and through ANOVA analysis the metabolites were determined to be significantly different (P-value<0.05) between the three groups. A multiple comparison table presented the group significant differences and LDA correctly classified the experimental groups with 100% accuracy. U937 and actively infected cells produced similar results to what was seen in other investigations where sera and plasma were used as metabolite source. Latently infected cells produced the more distinguishable separation among the experimental groups and the metabolites responsible for this separation were those mainly involved in glycolysis and lipid biosynthesis pathways. All the cell lines were treated with lactate to evaluate the influence of one prominent metabolite on the virus and cell metabolism. Lactate was selected because the metabolite was found to be significantly present in the initial experiments and for its role in glycolysis (indicates anaerobic respiration). Cysteine, an indicator of oxidative stress was produced and some of the metabolites such as alanine and taurine were no longer detectable. Conclusion: NMR spectroscopy successfully elucidated metabolic profiles of U937 cells, U1 cells (latent virus) and PMA induced U1 cells (active virus). The technique was highly reproducible with minimal sample preparation. Most metabolites that were detected are those primarily associated with metabolic disorders involving glycolytic energy metabolism. Through multiple comparisons it was determined that latent HIV-1 infection had a profound effect on cell glycolysis as seen by the significant alteration of lactate and the occurrence of aerobic glycolysis and mitochondrial disruption. In this study, it was observed that the virus supports biosynthetic pathways more than the production of energy through oxidative phosphorylation. Cells that were exposed to lactate produced a different metabolic profile from those that were not treated, this indicated that an increase or decrease in concentration of a particular metabolite can affect cell metabolism in HIV infected cells.
Dissertation (MSc)--University of Pretoria, 2017.
Technology Innovation Agency (TIA)
National Research Foundation (NRF)
Biochemistry
MSc
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Costiniuk, Cecilia T. "Oncolytic Viruses as a Potential Approach to Eliminate the HIV Reservoir." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23933.

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Similar to cancer cells, HIV-infected cells differ from HIV-uninfected cells in that they have altered interferon signaling pathways, the apparent reason for the selectivity of certain oncolytic viruses (OVs). Therefore, it was hypothesized that use of an OV, such as recombinant Maraba virus (MG1), may be a potential approach to eliminate latently-infected cells constituting the HIV reservoir while sparing HIV-uninfected cells. This was studied in U1, ACH-2, OM-10 and J1.1 cells and their respective HIV-uninfected parent cell lines in addition to CD4+CD25-HLADR- cells from HIV-infected individuals on effective antiretroviral therapy. Although MG1 infected and killed latently HIV-infected U1 cells to a greater degree than the HIV-uninfected parent U937 cells, this was not observed in the other HIV-infected cell lines and their respective parent cell lines. Furthermore, results from primary cells suggest that MG1 alone does not appear to eliminate cells which comprise the major HIV reservoir. Challenges of studying the HIV reservoir and priorities for future studies examining the use of OVs as a potential strategy to eliminate the HIV reservoir are discussed.

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35

Norton, Nicholas James. "Cellular and viral factors affecting HIV-1 silencing and reactivation." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/290018.

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Despite advances in the treatment of HIV-1 a cure remains elusive. A significant barrier to the eradication of the virus from an infected individual is a pool of cells infected with transcriptionally silent proviruses. A key pillar of the strategy to eradicate latent viruses has been called 'kick and kill', whereby the latent virus is stimulated to transcribe rendering the host cell vulnerable to eradication by cytotoxic T cells. Optimising the reactivation signal is therefore critical to this approach. Here the established model system of latency 'J-lat' is used to probe optimum reactivation signals. Single clones are observed to respond to maximal stimulation with a single agent with a fixed proportion of cells. Here it is shown that this proportion can be overcome by dosing with two agents in combination and critically that maximum synergies between agents occur at concentrations of agents close to those achieved in vivo. The role of SETDB1 recruitment by the recently described HUSH complex is examined using shRNA knockdowns of these proteins. Knockdown does not increase expression from the majority of J-lat clones tested. Viral factors which influence silencing and reactivation from latency have not been explored to the same extent. Here mutations affecting the binding of splicing factors to HIV-1 mRNA were cloned into laboratory viruses. A reduction in splice factor binding is seen to change the use of splice junctions required for the production of Tat mRNA; in turn this alters the rate at which proviruses are silenced. In addition the threshold for transcription in response to stimulation is increased in mutants with reduced splice factor binding.

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36

Cristina, Rocha Vilela Moura Líbia. "Teste tuberculínico e tratamento da tuberculose latente em uma coorte de pacientes com HIV/AIDS." Universidade Federal de Pernambuco, 2011. https://repositorio.ufpe.br/handle/123456789/6988.

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A identificação de pessoas soropositivas com tuberculose latente (TBL), através do teste tuberculínico e o tratamento preventivo para tuberculose (TB), estão incluídas nas recomendações para a assistência aos pacientes com HIV/Aids em todo mundo. No Recife, entre julho de 2007 e fevereiro 2010, acompanhou-se uma coorte de pacientes HIV/Aids atendidos em dois serviços de referência - o Hospital Correia Picanço e o Hospital Universitário Oswaldo Cruz, com os seguintes objetivos: descrever a freqüência de realização do TT e analisar os fatores associados a sua não realização, assim como os fatores associados à sua positividade em pacientes infectados pelo HIV; estimar a probabilidade dos pacientes não reatores ao primeiro teste não repetirem o TT, analisar os fatores associados ao tempo até sua repetição e analisar a efetividade do tratamento para TBL com isoniazida (INH) 300mg/dia, por seis meses, controlando os co-fatores potenciais de confusão. No primeiro estudo realizou-se um caso controle onde a variável dependente foi a realização do TT. No segundo estudo utilizou-se o método de Kaplan-Meier para estimar a probabilidade da não repetição do TT e o teste de Log Rank para verificar se houve diferenças entre as estimativas do Kaplan Meier para as categorias de cada variável do estudo. No terceiro estudo acompanhou-se uma coorte de pacientes com indicação de realizar o tratamento para TBL. Calculou-se densidade incidência para quem foi exposto a INH e para quem teve indicação e não foi exposto à INH e a razão entre as taxas (Hazard Ratio). Estimou-se a probabilidade de não ter TB pelo método de Kaplan Méier. Os principais resultados encontrados foram: 2.290 pacientes entraram na coorte, 1.087 (47,5%) realizaram o TT e 1203 (52,5%) não realizaram. Estiveram associados a não realização do TT: sexo masculino, idade menor de 39 anos, menos de nove anos de escolaridade, ganhar mais que um salário mínimo, ser usuário de crack e ser atendido no Hospital Universitário Oswaldo Cruz. Entre os 1.087 pacientes que realizaram o TT, a prevalência de positividade foi de 21,6% entre os pacientes com CD4 ≥ 200 e de 9,49% entre os pacientes com CD4 < 200 (p=0,002). Permaneceram associados ao TT ≥ 5 mm, no extrato de contagem de CD4 ≥ 200: uso de HAART, uso de Crack e ter menos de 10 anos de escolaridade. Dos 811 pacientes que tinham indicação de repetir o teste, 314 (38,7%) repetiram o TT. A probabilidade de não repetir o TT foi de 42%. Permaneceram associadas a não repetição do teste: idade, IMC, sexo e escola. 201 pacientes foram acompanhados para o estudo da efetividade do tratamento da TBL. Desses, 126 (62,7%) iniciaram o tratamento para TBL, e 75 pacientes (37,3%) não iniciaram. A taxa de incidência de tuberculose na coorte de indicação para TBL foi de 11,25/1.000 pessoa-ano. Considerando apenas os 75 pacientes que não iniciaram ou abandonaram o tratamento para TBL, a taxa de incidência de tuberculose foi de 29,67/1.000 pessoa-ano. A estimativa da probabilidade de desenvolver a tuberculose entre os pacientes com indicação de tratamento da TBL no final do estudo foi de 1,9%. Entre os que não o realizaram ou a fizeram de maneira irregular, a estimativa da probabilidade de desenvolver a tuberculose foi de 5,2%. Os resultados encontrados demonstraram que não houve uma adequada adesão nem para a realização do primeiro teste tuberculínico nem para a repetição do mesmo. É imprescindível que sejam revistas as recomendações com relação ao início do tratamento da TBL estar baseado na realização do teste tuberculínico

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Vidal, Júlia Souza. "Rifapentina no tratamento da infecção latente de tuberculose na população geral e em pessoas vivendo com HIV/AIDS : síntese das evidências." reponame:Repositório Institucional da UnB, 2014. http://repositorio.unb.br/handle/10482/16495.

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Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Saúde Coletiva, 2014.
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A infecção latente da tuberculose (ILTB) e a coinfecção com HIV são desafios para o controle da tuberculose. O objetivo do presente estudo foi avaliar e sintetizar as informações disponíveis na literatura sobre o tratamento da ILTB na população geral e em pessoas que vivem com HIV/AIDS para subsidiar a decisão do Programa Nacional de Controle da Tuberculose quanto à quimioprofilaxia secundária da ILTB. Foram pesquisadas as bases MEDLINE, Cochrane Library, Centre for Reviews and Dissemination, EMBASE, LILACS, SCIELO, Tripdatabase, National Guideline Clearinghouse e Portal de Teses e Dissertações para identificar revisões sistemáticas, ensaios clínicos randomizados e diretrizes clínicas que avaliassem o tratamento da ILTB. A qualidade das evidências de ensaios clínicos randomizados foi avaliada por meio da escala de Jadad, e a qualidade das recomendações de outras fontes de evidências por meio da abordagem do GRADE – Grading of Recommendations Assessment, Development and Evaluation. As evidências disponíveis sugerem que não há diferença entre o tratamento de curta duração com rifapentina e a terapia preconizada, de 6 meses de isoniazida, na redução da incidência de tuberculose ativa ou mortalidade. A adesão foi melhor com a administração de rifapentina diretamente observada em comparação à isoniazida autoadministrada. A qualidade da evidência é moderada ou baixa. Rifapentina é recomendada por uma diretriz com base nessa qualidade da evidência. Os dados disponíveis são escassos e de qualidade moderada ou baixa, e os estudos em andamento também são abertos. As evidências disponíveis podem parecer insuficientes para apoiar a incorporação de rifapentina para ILTB na população geral e em pessoas que vivem com HIV/AIDS, mas aspectos como taxa de adesão, viabilidade da implementação, custos e peculiaridades locais devem ser considerados no momento da decisão. __________________________________________________________________________ ABSTRACT
Latent tuberculosis infection (LTBI) and HIV-coinfection are challenges to tuberculosis transmission control. We aimed to assess and synthesize the information available in the literature regarding the treatment LTBI in both general and HIV-positive population to support the Brazilian Tuberculosis Control Program decision-making for LTBI secondary chemoprophylaxis. We searched MEDLINE, Cochrane Library, Centre for Reviews and Dissemination, EMBASE, LILACS, SCIELO, Tripdatabase, National Guideline Clearinghouse and Brazilian Thesis Repository to identify systematic reviews, randomized clinical trials and clinical guidelines that assessed the LTBI pharmacological treatment. Quality of evidence from randomized clinical trials was assessed by using Jadad Scale and recommendations from other evidence sources by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The available evidences suggest that there are no differences between rifapentine short course treatment and the standard 6-month therapy with isoniazid in reducing active tuberculosis incidence or death. Adherence was better with directly observed therapy rifapentine compared to self-administered isoniazid. The quality of evidence is moderate or low. Rifapentine is recommended by one guideline based on this quality of evidence. Evidence available is scarce and of moderate or low quality, and ongoing trials are design as open label. Available evidences may seem insufficient to support rifapentine incorporation for LTBI in general and HIV-positive populations, but aspects such as adherence rates, implementation feasibility, costs and local particularities should be considered in the decision-making process.

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Sears, Jacqueline L. "Machismo as a Determinant for HIV/STD Risk Behavior Among Latino MSM." Available to VCU users at:, 2006. http://hdl.handle.net/10156/1896.

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Doolabh, Deelan Sudhir. "The Influence of HIV-1 Subtype C LTR Genotype on Latency Potential." Master's thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/29620.

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The persistence of latent viral reservoirs, that are insensitive to antiretroviral therapy (ART), remains the greatest barrier to HIV-1 eradication. The role that viral factors play in HIV-1 latency establishment and maintenance is poorly understood, and characterisation of these factors is imperative for the development of curative strategies or interventions that could lead to HIV-1 remission in infected individuals. Subtype level genotypic variation within regulatory elements of the HIV-1 promoter, the long terminal repeat (LTR), has been shown to influence latency establishment in in vitro models. We investigated the influence of inter-participant subtype C LTR genotypic variation on the establishment of latency in a dual reporter HIV-1 plasmid model and evaluated potential correlates of this latency potential. Long terminal repeats from 11 ART-naïve, acutely subtype-C infected women in the CAPRISA 004 cohort from Durban, South Africa were cloned into an HIV-1-expressing vector (pRGH) used to generate pseudovirions following HEK293T transfection. Pseudoviruses harboured a gag-eGFP gene under the control of the participant LTR, allowing measurement of active replication, and an mCherry gene under the control of a constitutive CMV promoter allowing measurement of viral integration. Latency potential was expressed as the ratio of mCherry only (latent) to eGFP and mCherry (active replication), as measured by flow cytometry after infection of Jurkat E6-1 and CEM.NKR CCR5+ cell lines before and after T cell activation with PMA/Ionomycin. A panel of LTRs cloned into a pGL4.10 luciferase expression vector were used to measure basal LTR expression and Tat-induced LTR expression. All LTR sequences were classified as subtype C, with an average inter-participant pairwise DNA distance of 7.6%. The median basal LTR activity was approximately two times higher than that of the BaL isolate (interquartile range: 1.38-2.14), and Tatinduced activity approximately nine times higher than that of BaL (interquartile range: 6.16-10.33). We observed consistently greater proportions of latently infected cells than actively infected cells. In Jurkat E6-1 cells, the median latent:active infection ratio was 1.97 (range 0.86-2.83; three experiments). Latency was reversible in a proportion of cells as the median latent:active infection ratio decreased to 0.55 (range 0.46-0.78). The latent:active ratio was unchanged, post-stimulation, in CEM.NKR CCR5+ cells and was therefore found not to be a suitable cell-line for the model. Latency potential did not correlate with basal or Tat-induced activity (Spearman correlation tests, basal p=0.25, r=-0.38, Tat-induced p=0.42, r=-0.27). The DNA distance in characterised functional sites from consensus did not correlate with latency potential (Spearman correlation test p=0.67, r=0.14). Our data suggest that HIV-1 LTRs have intrinsic properties which influence latency potential and the proportion of latently infected cells early post-infection. However, since differences were independent of basal and Tat-induced LTR activity, other factors such as regulatory element interaction and the efficiency of recruitment of molecules responsible for establishing latency, such as histone modifiers, may play a role.

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40

Sheehan, Diana M. "Neighborhood-level Determinants of Delayed HIV Diagnosis and Survival among HIV-positive Latinos, Florida 2000-2011." FIU Digital Commons, 2016. http://digitalcommons.fiu.edu/etd/2502.

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The purpose of this study was to estimate disparities in late human immunodeficiency virus (HIV) diagnosis and all-cause mortality among varying populations of HIV-positive Latinos, and to identify neighborhood-level predictors. Florida HIV surveillance data for years 2000–2011 were merged with 2007–2011 American Community Survey (ACS) data. Multilevel logistic regressions were used to estimate adjusted odds ratios (aOR) for late HIV diagnosis (acquired immunodeficiency syndrome within 3 months of HIV diagnosis). Multilevel weighted Cox regressions were used to estimate adjusted hazard ratios (aHR) for mortality. Of 5522 Latinos diagnosed 2007–2011, males were at increased odds of late diagnosis compared with females (aOR 1.37, 95% confidence interval [CI] 1.13-1.67). Associated factors included residing in the lowest quartile of neighborhood education for females, and in the 3 highest quartiles of unemployment for males. Foreign-born compared with United States (US)-born Latinos were also at risk (aOR 1.24, 95% CI 1.08-1.42). Among foreign-born, residing in areas with

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Nguyen, Kien. "EPIGENETIC REGULATION OF HIV-1 LATENCY BY HISTONE H3 METHYLTRANSFERASES AND H3K27 DEMETHYLASE." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1491495889537421.

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Carvalho, Carlos Gilvan Nunes de. "Fatores clínicos e epidemiológicos associados à sífilis, à toxoplasmose e à tuberculose latente em pacientes com HIV em um ambulatório especializado no Piauí." reponame:Repositório Institucional da FIOCRUZ, 2015. http://beta.arca.fiocruz.br/handle/icict/14502.

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Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Teresina, PI, Brasil
INTRODUÇÃO: Apesar da redução da morbidade e mortalidade por doenças relacionadas à AIDS, alguns aspectos epidemiológicos das coinfecções com o vírus da imunodeficiência humana (HIV) ainda precisam sem melhor compreendidos. O HIV compartilha mecanismos de transmissão semelhantes aos da sífilis, doença bacteriana provocada pelo Treponema pallidum. O HIV pode contribuir com manifestações clínicas atípicas e apresentar dificuldades de respostas no tratamento da sífilis. As coinfecções com as formas latentes do bacilo Mycobacterium tuberculosis (ILTB) ou do parasito Toxoplasma gondii podem acarretar risco de desenvolvimento das doenças ativas sintomáticas, como a tuberculose e a neurotoxoplasmose, resultantes da imunossupressão pelo HIV. OBJETIVO: Este trabalho teve como objetivo avaliar as características clínico-epidemiológicas de um grupo de pacientes com HIV atendidos em um Serviço de Atenção Especializada (SAE) em Teresina, Piauí, e estimar a reatividade aos testes diagnósticos para agentes infecciosos da toxoplasmose, da sífilis e da ILTB, além de avaliar a associação desses fatores com essas coinfecções. MÉTODO: Foi realizado um estudo de série de casos, onde foram revisados os prontuários através de coleta de dados secundários, no período de junho a agosto de 2015. Foram incluídos no estudo 134 pacientes acompanhados entre os anos de 2009 e 2015. As variáveis independentes foram analisadas e tiveram suas médias, frequências e respectivas medidas de dispersão calculadas, considerando-se as reatividades aos testes diagnósticos como variáveis dependentes. A análise dos fatores associados foi realizada para cada coinfecção por modelos bivariados e de regressão multivariada RESULTADOS: Houve uma predominância de pacientes no sexo masculino (67,91%), com idades preferenciais no adulto jovem (65.67% de 30 a 59 anos), boa escolaridade e elevada média de contagem de LT-CD4 (565,58 células/mm3). A toxoplasmose manteve associação com significação estatística para indivíduos com 40 ou mais anos e com a ausência de dependência química, dislipidemia e tuberculose ativa. A sífilis manteve associação com presença de esteatose hepática, renda mensal de até 1 salário mínimo (SM) e entre homens que fazem sexo com homens (HSH). A ILTB, manteve-se associada a ausência de fossa séptica. CONCLUSÕES: A toxoplasmose, a sífilis e a ILTB são condições frequentes em pacientes com HIV em tratamento ambulatorial. Estas infecções estão associadas a fatores relacionados às suas vias de transmissão, o que aponta para a necessidade de adoção de medidas para sua prevenção neste grupo de pacientes
Despite the reduction in morbidity and mortality from AIDS-related illnesses, some epidemiological aspects of co-infections with the human immunodeficiency virus (HIV) still need without better understood. HIV share transmission mechanisms similar to those of syphilis, bacterial disease caused by Treponema pallidum. HIV can contribute to atypical clinical manifestations and present difficulties for answers in the treatment of syphilis. The co-infections with latent forms of the bacillus Mycobacterium tuberculosis (LTBI) or Toxoplasma gondii parasite can cause risk of developing symptomatic active disease, such as tuberculosis and toxoplasmosis immunosuppression resulting from HIV. OBJECTIVE: This study aimed to evaluate the clinical and epidemiological characteristics of a group of patients with HIV treated at a Specialized Care Service (SCE) in Teresina, Piauí, and estimate the reactivity to diagnostic tests for infectious agents of toxoplasmosis, syphilis and of LTBI, and to evaluate the association of these factors with these co-infections. METHOD: A study was conducted series of cases where records were reviewed by collecting secondary data, in the period from June to August 2015. The study included 134 patients followed between 2009 and 2015. The independent variables were analyzed and had their averages, frequencies and their calculated measures of dispersion, considering the reactivity to diagnostic tests as dependent variables. The analysis of associated factors was performed for each coinfection by bivariate and multivariate regression models RESULTS: There was a predominance of patients in males (67.91%), with preferential ages in young adults (65.67% 30-59 years), good education and high average LT-CD4 count (565.58 cells / mm3). Toxoplasmosis continued association with statistical significance for individuals with 40 or more years and the lack of addiction, dyslipidemia and active tuberculosis. Syphilis continued association with the presence of hepatic steatosis, monthly income of up 1 minimum wage (MW) and among men who have sex with men (MSM). The LTBI, remained associated with the absence of septic tank. CONCLUSIONS: toxoplasmosis, syphilis and LTBI are common conditions in HIV patients in outpatient treatment. These infections are associated with factors related to their transmission routes, which highlights the need to adopt measures for its prevention in this group of patients

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Pearson, Richard. "Epigenetic Silencing of HIV Transcription Through Formation of Restrictive Chromatin Structures at the Viral LTR Drives the Progressive Entry of HIV into Latency." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1223040734.

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Mates, Jessica Marie. "TRANSCRIPTIONAL REGULATION OF HIV-1." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1395845500.

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45

Huot, Nicolas. "Relation entre l’expression des LAT et du gène RL2 pendant la latence du virus HSV-1." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114860/document.

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Le virus de l’herpès simplex de type 1 (HSV1) établit une infection latente dans le système nerveux de l'homme, au cours de laquelle un type de transcrits, appelés LATs (pour latency associated transcripts), s'accumule dans les neurones infectés. Le rôle clef des LATs dans le contrôle de la latence virale est reconnu. Cependant, depuis leur découverte dans les années 80, leur mécanisme d'action reste non élucidé.Le gène des LATs est transcrit en un LAT primaire de 8,3kb, qui est épissé, conduisant à la formation de deux LATs stables : le LAT2kb et le LAT1.5kb. De façon remarquable, le LAT2kb et le LAT1.5kb sont des introns. Leur stabilité est la conséquence d'un branchement non canonique qui se traduit par le maintien de la structure en lariat. Par ailleurs, la région du génome codant les LATs contient également le gène RL2 qui code ICP0, la protéine la plus en amont dans la cascade de réactivation du virus. Des études précédentes ont montré qu’au moment de la latence, des transcrits RL2 non épissés, s'accumulent au site principal de la latence (le ganglion de Gasser).Nous avons caractérisé ces transcrits non épissés du gène RL2 dans les tissus infectés de façon latente. Ils contiennent de façon reproductible l’intron 1 et sont d’autant plus abondants dans les tissus infectés de façon latente que les LAT s’accumulent. On peut ainsi distinguer plusieurs types de tissus infectés de façon latente, dont les deux exemples les plus représentatifs sont d’une part le ganglion de Gasser (forte expression des LAT et accumulation de transcrits RL2 non-épissés) et d’autre part le ganglion cervical supérieur (pas d’accumulation de LAT par rapport aux quantités exprimées pendant la phase aiguë de l’infection, et très peu d’expression dans transcrits non-épissés). Dans tous les cas, la réalité du caractère latent de l’infection était confirmé par la présence de génome viral sans expression de transcrits matures de gène viral précoce (représenté par celui de la thymidine kinase) ni tardif (gène UL18). Ces résultats suggèrent une relation entre la présence des LAT et l’accumulation de transcrits RL2 non-épissés, ce qui pourrait être en relation avec le maintien de l’infection à l’état latent dans ces tissus
The herpes simplex virus type 1 (HSV-1) establishes a latent infection in the nervous system of humans, in which latency associated transcripts (LATs) accumulate in infected neurons. The key role of LATs in the control of viral latency is well established. However, since their discovery in the 80s, their mechanism of action remains unclear.The LAT gene is transcribed into a 8.3 kb primary LAT that is rapidly spliced, leading to the formation of two stable LATs; LAT2kb and LAT1.5kb. Remarkably, the LAT2kb and LAT1.5kb are introns. Their stability is the result of a non-canonical sequence of the branching point, which results in maintaining the lariat structure.Moreover, the region of the genome encoding the LATs also contains the RL2 gene, encoding ICP0 that acts upstream in the cascade of viral reactivation. Previous studies have shown that RL2 unspliced transcripts may accumulate in the main site of HSV-1 latency (trigeminal ganglia). We have characterized these unspliced transcripts RL2 gene in latently infected tissues. They reproducibly contain intron 1 and are particularly abundant in latently infected tissues where LATs also accumulate. We distinguished several types of latently infected tissues, the two most representative examples being the trigeminal ganglion (strong expression of LATs and accumulation of non-spliced transcripts RL2) and, in the opposite, the superior cervical ganglion (no accumulation of LAT compared with the amounts expressed during the acute phase of infection, and little expression in non-spliced RL2 transcripts). In all cases, the reality of the latent nature of the infection was confirmed by the presence of viral genome with no expression of mature transcripts from early viral gene (represented by the thymidine kinase gene) or late (UL18 gene).These results suggest a relationship between the presence of LAT and the accumulation of non-spliced RL2 transcripts, which could be related to the maintenance of latent infection in these tissues

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Elbezanti, Weam Othman. "The Effect of Mutating RUNX1 Binding Site on HIV-1 Replication and Novel HIV-1 Latency Reversal through Using Clinically Prescribed Benzodiazepines." Thesis, University of the Sciences in Philadelphia, 2019. http://pqdtopen.proquest.com/#viewpdf?dispub=13862426.

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The major barrier to curing HIV-1 infection is latency. HIV-1 latent cells are those in which the viral genome has been integrated into the host cell genome but the virus does not produce the primary infectious agents, viral RNA and proteins. Latency can occur when the virus directly infects long-lived memory CD4+ T cells or infects active CD4+ T cells that have the potential to become memory T cells. The virus persists inside those cells as long as they are alive. This dormancy provides a reservoir of HIV-1 virus in memory T cells, which can cause infection relapse whenever antiretroviral therapy (ART) is discontinued. The situation is further complicated by the fact that multiple reservoirs of HIV-1 virus can be established at early stages of infection.

The major reservoir lies in the CD4+ T cells present in blood, lymph nodes and the spleen. Unfortunately, ART fails to target hidden HIV-1 virus that persists in resting T-cells. Furthermore, life-long ART use increases the chances that mutant virus will develop which will be resistant to continued therapy. Therefore, various studies have explored mechanisms to eradicate the latent HIV-1 reservoir. One proposed strategy to target this reservoir is known as “shock and kill”. The proposed shock and kill strategy initially “shocks” the HIV-1 virus out of latency with latency reversing agents (LRAs). The reactivated virus can then be controlled by ART and cytotoxic CD8+ T cells (CTLs), which kill the infected cells. Despite the great findings regarding reactivating HIV-1 latency in vitro and ex vivo, tested LRAs proved unsuccessful in reactivating HIV-1 virus in clinical trials.

Different factors can contribute to establishment of HIV-1 latency and different reservoirs in different immune cells and tissues are established early after HIV-1 infection. Therefore, synergy between multiple LRAs should be sought and studied for successful reactivation of the latent viral pool.

Runt Related Transcription Factor 1 (RUNX1) is a key transcription factor that is important during T cell development and has been shown to recruit different transcription factors in a context dependent manner. It has been shown to be involved in repressing various genes and it also interacts with chromatin modifiers that can alter the landscape of the chromatin and modify its compaction. Our lab has shown that there is a putative RUNX1 binding site on HIV-1 long terminal repeats (LTR) and the transfection of RUNX1 can suppress HIV-1 transcription. In addition, our lab has shown that the benzodiazepine, RO5-3335, which pharmacologically inhibits RUNX1, synergizes with vorinostat (SAHA), an HDAC inhibitor to reactivate latent HIV-1.

Using DNA cloning, an HIV-1 virus with a mutated RUNX1 binding site was constructed. Then, replication, infectivity and fitness of the mutated virus were examined and compared to a control virus using ELISA, RT, PCR, and TA cloning techniques. We have found that this mutated virus replicates faster and has more fitness and infectivity than the control virus with an intact RUNX1 binding site. Our results show that inhibition of RUNX1 binding to HIV-1 3’ long terminal repeat (LTR) positively affects viral replication and infectivity. This suggests that RUNX1 host transcription factor suppresses HIV-1 replication through its transcriptional repressor function and it possibly contributes to establishment of latency.

We screened clinically prescribed benzodiazepines (BDZs) to identify reactivators for latent HIV-1 virus. Using flow cytometry, we have found most of these BDZs synergized with SAHA in reactivation of latent HIV-1. Unlike the other BDZs tested, alprazolam was able to reactivate HIV-1 even when not in combination with SAHA. The effect of alprazolam on RUNX1 responsive genes was further investigated using qPCR. Alprazolam was found to affect RUNX1 responsive genes similarly to RO5-3335, a known RUNX1 inhibitor. The effect of alprazolam on IFNγ and TNFα that are produced from cytotoxic T cells (CTLs) was also examined. Alprazolam enhanced CTL function that was shown in the literature to be attenuated by SAHA. Thus, alprazolam successfully reverses HIV-1 latency and decreases the side effects of SAHA on CTL function when used in combination.

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Paganella, Machline Paim. "Associação da incidência de dislipidemia e anormalidades de glicose com o tratamento antirretroviral em uma coorte de crianças infectadas pelo HIV na américa latina (NISDI/PLACES)." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2014. http://hdl.handle.net/10183/104126.

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Kussen, Gislene Maria Botão. "Análise do ensaio imunológico igra versus prova tuberculínica para detecção de infecçção latente por Mycobacterium tuberculosis em pacientes HIV positivos." reponame:Repositório Institucional da UFPR, 2014. http://hdl.handle.net/1884/36972.

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Orientadora: Profª. Drª. Sonia Mara Raboni
Co-orientadora: Profª. Drª. Libera Maria Dalla Costa
Dissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Medicina Interna. Defesa : Curitiba, 31/10/2014
Inclui referências
Resumo: Indivíduos infectados com M. tuberculosis (MTB) sem doença ativa têm infecção latente por tuberculose (ILTB). Pacientes portadores de HIV, por serem imunodeprimidos, são mais propensos a desenvolver TB ativa. A identificação da ILTB permite a intervenção precoce com o uso de quimioprofilaxia e, consequentemente, contribui para uma menor morbidade e mortalidade neste grupo de pacientes. A prova tuberculínica (PT) mantém-se como o método padrão-ouro para diagnóstico de ILTB, apesar de apresentar limitações técnicas. O objetivo deste estudo foi avaliar o desempenho do teste imunológico QuantiFERON TB Gold In Tube®, que se baseia na avaliação da resposta do gama interferon para antígenos específicos de MTB, para diagnóstico de ILTB em pacientes com HIV residentes em um país com alta incidência de tuberculose, comparando estes achados com os resultados da PT. Realizou-se um estudo de Coorte, que incluiu 140 pacientes, que foram acompanhados por um período médio de 12 meses (6 a 21 meses). Um total de 115 (82%) e nove (6,4%) pacientes apresentou ambos os testes negativos e positivos, respectivamente. Entre os resultados discordantes observou-se em 12 (8,6%) pacientes IGRA positivo com PT negativa e em quatro (3%) pacientes resultados de IGRA negativo com PT positiva. O coeficiente de Cohen Kappa foi de 0,214, mostrando uma concordância pobre entre as duas técnicas. Comparando os resultados obtidos em ambos os testes, pode-se verificar que não houve evidência estatística de que um ou outro método seja superior (p = 0,08). Não foi observada nenhuma correlação entre os resultados de IGRA e PT e os valores de LT CD4+, embora em pacientes com maior imunossupressão (LT CD4+ <300 células/mm3) observamos testes IGRA positivos e PT não reatoras. No período de acompanhamento, um paciente que apresentava PT e IGRA negativos evoluiu para morte por septicemia, e outro com resultados discordantes (IGRA+/PT-) apresentou conversão da PT. Avaliando as características de desempenho do IGRA, considerando PT como o teste padrão-ouro, a sensibilidade observada foi em torno de 70%, com especificidade de 90%. Considerando os resultados de ambos os testes como verdadeiro positivo, um aumento de 8% na positividade pode ser observado. O tratamento da ILTB neste grupo de pacientes poderá ter impacto sobre a taxa de tuberculose ativa e sobrevivência de portadores do HIV, porém isso ainda precisa ser avaliado ao longo dos anos. Palavras-chave: HIV, Mycobacterium tuberculosis, teste tuberculínico
Abstract: Individual infected with M. tuberculosis (MTB) without active disease can present latent tuberculosis infection (LTBI). These patients in the context of impaired immune systems, such as HIV+, are more likely to progress to active TB. Identification of LTBI allows early intervention with the use of chemoprophylaxis, consequently contributing to a lower morbidity and mortality in this group of patients. Tuberculin skin test (TST) has remained as gold standard method to diagnosis LTBI, despite it presents technical limitations. The aim of this study was to assess the performance of the new immunological test Quantiferon TB Gold in tube, which is based on evaluating the IFN-gamma response to specific MTB antigens, to LTBI diagnosis on HIV patients from a country with high-tuberculosis burden, comparing the findings with TST results. It was a cohort study that included 140 patients, who are followed up for 21 months. A total of 115 (82%) and 9 (6.4%) patients had both tests negative and positive, respectively. Disagreement results occurred in 12 (8.6%) patients, whom had IGRA positive with negative TST and 4 (3%) patients that showed positive TST with negative IGRA. The Cohen Kappa coefficient found was 0.214, showing a poor concordance between both techniques. Comparing the results obtained by both tests, there was no statistical evidence that either method is different, because of the discrepancies occurred in a statistically identical manner (p = 0,08). None correlation between the results and CD4+ LT values was observed, though in patients with lowers CD4+ LT values (<300 cell/mm3) only IGRA tests were positive. In the period of follow up one patient, that presented both negative tests, evolved to death from sepsis, and another with discordant results (IGRA+/TST-) presented TST conversion. Evaluating the operational characteristics of IGRA, considering TST as the gold standard test, the sensitivity observed was around 70% and the specificity 90%. Considering the results of both tests as true positive an incremental of 8% in the positivity could be observed. If the LTBI treatment in this group of patients will have some impact on the rate of active tuberculosis and survival of HIV carriers still need to be evaluated over the years. Keywords: HIV, Mycobacterium tuberculosis, tuberculin skin test.

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García, Vidal Edurne. "Identification and characterization of novel latency-reversing agents to clear HIV-1 viral reservoir." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/669732.

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La terapia antirretroviral ha cambiado la perspectiva sobre la infección por VIH-1 de enfermedad letal a crónica. Aun así, el reservorio latente del VIH-1 es una de las mayores barreras para lograr una cura. La estrategia “shock and kill” se basa en inducir la transcripción viral del provirus latente del VIH-1 seguido de la muerte selectiva de las células reactivadas. Aunque muchos agentes reversores de la latencia (LRAs) han sido identificados y testados, ninguno ha logrado erradicar eficazmente dicho reservorio. Dada la necesidad de nuevos agentes y estrategias capaces de eliminar el reservorio latente, hemos propuesto moduladores de la respuesta inmune innata o del ciclo celular para dicho fin. El estudio de moduladores de la inmunidad innata puede representar una alternativa dadas sus funciones intrínsecas, i. e., protección y eliminación de infecciones. Acitretina, regulador de la inmunidad innata aprobado contra la psoriasis, ha sido propuesto como inductor de la reactivación del VIH-1 y la muerte de las células infectadas. A pesar de ello, el efecto de acitretina en la reactivación fue muy modesto en la mayoría de modelos celulares que testamos, aunque se detectó la activación de la vía de RIG-I, y una ligera inducción de la reactivación viral en un modelo no clonal de células T. Además, acitretina tampoco promovió la eliminación de las células infectadas. Los compuestos anti-cáncer también han sido propuestos como estrategia contra el reservorio, debido a la habilidad de ciertos agentes para modificar la transcripción génica o promover la apoptosis. El cribado de una librería de compuestos anti-cancer reportó varias dianas cuya inhibición reactivó el VIH-1, incluyendo histona deacetilasas (HDACs), Janus quinasas (JAKs), IκB quinasas (IKKs) y proteínas “heat-shock” (HSPs). Entre los nuevos LRAs identificados, los inhibidores de Aurora kinasas (AURKi) representaron la mayor familia de compuestos, no descritos como LRAs, que mostraron capacidad de reactivación del VIH-1 de forma significativa y consistente. Los AURKi mejoraron la reactivación mediada por los HDACi, sugiriendo la habilidad para reactivar distintos provirus insertados. Curiosamente, AURKi restringió la replicación aguda del VIH-1, insinuando un papel dual para dichos compuestos en la infección por VIH-1. Midostaurin, un inhibidor de multi-quinasas aprobado contra la leucemia, también se identificó como LRA. Midostaurin reactivó el VIH-1, tanto por si solo como en combinación con otros LRAs, corroborando previos reportes que asociaron esa actividad con la activación de la vía de NF-κB. Además, también se observó una inhibición de la infección aguda del VIH-1 en células primarias dependiente de SAMHD1 no descrita. El hecho de que los AURKi y midostaurina mejoren la reactivación del VIH-1 en combinación con otros LRAs, corrobora la idea de que distintos compuestos pueden ser necesarios para reactivar todos los provirus integrados, presentando así distintas especificidades para la reactivación del provirus que dependan de su lugar de integración en el genoma. Estas observaciones plantean dudas sobre los modelos usados para estudiar la latencia del VIH-1, pues los modelos clonales podrían ser inadecuados por la falta de heterogeneidad de lugares de integración. En conjunto, nuestros resultados sugieren que la modulación de la inmunidad innata y ciclo celular podrían incluirse en el desarrollo de futuros LRAs para la estrategia “shock and kill”; aun así, investigaciones adicionales siguen siendo necesarias con tal de avanzar hacia la cura del VIH-1.
Current antiretroviral therapy has changed the perspective of HIV-1 infection from a lethal illness to a chronic disease. However, the HIV-1 latent reservoir is a major hurdle to achieve a cure for HIV-1. The “shock and kill” strategy is based on inducing viral transcription of latent HIV-1 provirus followed by the selective killing of reactivated cells. Although several latency-reversing agents (LRAs) have been identified and tested, none of them has been able to efficiently eradicate the HIV-1 latent reservoir. Based on the need of novel agents and strategies to efficiently clear the latent reservoir, we evaluated compounds developed as modulators of the innate immune response or designed to modulate the cell cycle progression as novel agents able to purge the viral reservoir. The study of innate immune modulators as agents able to clear the HIV-1 reservoir might represent an alternative due to its intrinsic functions, i. e., protection and clearance of infections. The innate immune regulator acitretin, an FDA-approved compound for psoriasis, has been proposed to induce HIV-1 reactivation and selective killing of the infected cells. However, the effect of acitretin on HIV-1 reactivation was negligible in the vast majority of models tested, albeit activation of RIG-I pathway was detected and a mild induction of viral reactivation was observed in a non-clonal T cell model. Moreover, acitretin treatment did not induce the selective killing of the infected cells. Anti-cancer compounds have also been proposed as candidate therapies targeting the latent reservoir, mainly due to the ability of certain agents to modify gene transcription or to promote cell apoptosis. The assessment of the HIV-1 reactivation potential of an anti-cancer compound library reported several molecular targets whose inhibition promoted HIV-1 latency reversal, including the histone deacetylases (HDAC), Janus kinases (JAK), IκB kinases (IKKs) and heat shock proteins (HSPs). Among the new identified LRAs, Aurora kinases inhibitors (AURKi) represented the largest family of compounds not previously described as LRA that significantly and consistently showed HIV-1 reactivation capacity. AURKi were able to enhance the HDACi-mediated reactivation, suggesting that AURKi are able to target a distinct set of integrated provirus than that reactivated by the well-described HDAC inhibitors. Interestingly, AURKi restricted acute HIV-1 infection, suggesting a dual role for these compounds on HIV-1 infection. Midostaurin, a multi-kinase inhibitor approved for leukemia treatment, was also identified as an LRA. Midostaurin induced HIV-1 latency reactivation, either alone or in combination with other LRAs, consistent with previous reports that associated this activity with the activation of the innate immune NF-κB pathway. Moreover, we also observed a non-yet-reported and SAMHD1-dependent inhibitory effect of HIV-1 replication in primary cells. The enhanced capacity to promote HIV-1 reactivation of AURKi and midostaurin in combination with other LRAs supports the idea that different agents are needed to reactivate all latent provirus, presenting different specificities towards HIV-1 provirus reactivation depending on its integration site in the host genome. Furthermore, these observations also raise concerns on the models used to study HIV-1 latency, as clonal models might not be suitable due to the lack of heterogeneity in proviral insertion site, characteristic of non-clonal models. Altogether, our results suggest that modulation of innate immunity and cell cycle may be taken into account for the design of future LRAs for the “shock and kill” strategy; however, further research is still necessary before it can lead to an HIV-1 cure.

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Wang, Ling, Guang Y. Li, Jonathan P. Moorman, and Shunbin Ning. "MicroRNA Regulation Of Viral Immunity, Latency, And Carcinogenesis of Selected Tumor Viruses and HIV." Digital Commons @ East Tennessee State University, 2015. https://doi.org/10.1002/rmv.1850.

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MicroRNAs (miRNAs) function as key regulators in immune responses and cancer development. In the contexts of infection with oncogenic viruses, miRNAs are engaged in viral persistence, latency establishment and maintenance, and oncogenesis. In this review, we summarize the potential roles and mechanisms of viral and cellular miRNAs in the host-pathogen interactions during infection with selected tumor viruses and HIV, which include (i) repressing viral replication and facilitating latency establishment by targeting viral transcripts, (ii) evading innate and adaptive immune responses via toll-like receptors, RIG-I-like receptors, T-cell receptor, and B-cell receptor pathways by targeting signaling molecules such as TRAF6, IRAK1, IKKε, and MyD88, as well as downstream targets including regulatory cytokines such as tumor necrosis factor α, interferon γ, interleukin 10, and transforming growth factor β, (iii) antagonizing intrinsic and extrinsic apoptosis pathways by targeting pro-apoptotic or anti-apoptotic gene transcripts such as the Bcl-2 family and caspase-3, (iv) modulating cell proliferation and survival through regulation of the Wnt, PI3K/Akt, Erk/MAPK, and Jak/STAT signaling pathways, as well as the signaling pathways triggered by viral oncoproteins such as Epstein-Barr Virus LMP1, by targeting Wnt-inhibiting factor 1, SHIP, pTEN, and SOCSs, and (v) regulating cell cycle progression by targeting cell cycle inhibitors such as p21/WAF1 and p27/KIP1. Further elucidation of the interaction between miRNAs and these key biological events will facilitate our understanding of the pathogenesis of viral latency and oncogenesis and may lead to the identification of miRNAs as novel targets for developing new therapeutic or preventive interventions.

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Dissertations / Theses on the topic 'Latent HIV'

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