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Huang, Kenneth Hsing-Chung. "Immune correlates of viral control in chronic HIV infection." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111908.
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There are currently an estimated 33.2 million people living with human immunodeficiency virus (HIV) worldwide. For these individuals, long-term use of combination antiretroviral therapy (cART) is not feasible for a variety of reasons including major adverse complications, multi-drug resistance, poor adherence, and high cost. Hence, development of novel therapeutic strategies that can reduce the life-long dependency on cART is highly desired. In order to develop effective therapeutic strategies such as a therapeutic vaccine, we need to have a greater understanding of the immune correlates of viral control in chronic HIV infection. In this thesis, we used treatment interruption (TI) as a tool to test the efficacy of several therapeutic approaches and immune parameters for their association with effective control of viral replication.In Chapter 2 we showed that cART intensification and Remune vaccination resulted in reduced viral load (VL) plateau during sequential TIs. Although HIV-specific immune responses measured by interferon-gamma (IFN-gamma) enzyme-linked immunospot assay (ELISPOT) increased in the same time frame, neither their breadth nor magnitude correlated with the decrease in VL plateau. In Chapter 3 the effect of ALVAC-vCP1425 plus Remune vaccination on HIV proteome-wide HIV-specific responses was monitored using a dual color IFN-gamma/interleukin-2 (IL-2) ELISPOT assay. We observed an increase in the magnitude of HIV-specific IFN-gamma/IL-2 responses, as well as in the breadth of Gag-specific IFN-gamma responses in the vaccinated groups compared to placebo groups. A shift towards an increased contribution of Gag-specific responses to total HIV-specific vaccine induced immune response was associated with longer delay to viral rebound during TI. In Chapters 4 and 5, we examined baseline pre-TI immune parameters and their association with viral rebound and CD4 count change during TI in HIV-infected individuals in the chronic phase of infection experiencing virologic failure before TI (Chapter 4) or with different levels of VL control while on therapy prior to TI (Chapter 5). We saw that chronic antigen stimulation from persistent viremia as well as co-infections such as with cytomegalovirus are associated with T-cell senescence, which may result in less favourable clinical outcomes during TI.
Consequently, results from this thesis contribute to further understanding of immune correlates of viral control in chronic HIV infection. New therapeutic vaccines and interventions should induce polyfunctional HIV-specific immune responses, broad Gag-specific immune responses, as well as reducing chronic antigen stimulation to prevent irreversible T-cell exhaustion. Taken together, these insights could potentially lead to the development of novel treatment interventions that could effectively control viral replication off cART.
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Rowland-Jones, Sarah Louise. "The role of class I MHC molecules in the presentation of viral antigens to cytotoxic T lymphocytes." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296832.
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Azizi, Ali. "Humoral and cellular immune responses in RNA viral infections: Immunogenicity of HIV-1, HCV and SARS-CoV candidate vaccines in animal models." Thesis, University of Ottawa (Canada), 2006. http://hdl.handle.net/10393/29278.
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It is difficult to induce protective immunity against most RNA viruses. However, there is strong evidence that humoral and especially cellular immune responses play crucial roles in the control of established RNA viral infections. Thus, an ideal vaccine should be able to induce strong specific antibody titer as well as a robust T-helper and T-cell cytotoxic response. Here, correlates of protective immunity against HIV-1, HCV and SARS-CoV were assessed.
Monocistronic and polycistronic DNA constructs containing structural HIV-l, and SARS genes were designed. The structural proteins (HIV- gpl20, gag, pol, HCV-core, E1/E2 and SARS-NC) were also expressed, purified and characterized in mammalian and bacterial cell lines. HLA-A2.1 and B6 mice were immunized with different combinations of DNA constructs, recombinant proteins and novel adjuvants. Humoral responses were measured by titrating of specific antibodies and cell-mediated immune responses were identified by Th1/Th2 cytokine expression, lymphocyte proliferation, intracellular cytokine staining, HLA-peptide dimer assay, and ELISPOT. The first study in HIV-1 showed that a combination of DNA single constructs, protein and adjuvant induce a higher immune response compared to the DNA or/and protein alone. In the second HIV-1 approach, a synergistic effect between HIV/HCV antigens was detected that may lead to induction of multi-specific immune responses against both HIV and HCV. In the third study (SARS project), a high level of specific SARS-CD8+ T-cell response was demonstrated in mice that received DNA encoding the SARS-nucleocapsid, protein and XIAP (X-link inhibitor of apoptosis) as an adjuvant.
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Ogbu, Stella Chinyere. "Role of Topoisomerase II alpha in DNA Topology and T cell responses during Chronic Viral Infections." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etd/3661.
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The clearance of viruses is largely dependent upon the activation of T cells to generate a robust immune response. However, host responses are suppressed during chronic viral infections. In this thesis, we explored the role of Top2α in DNA topology in individuals with chronic HBV, HCV, and HIV infections. We found that Top2α protein expression and activity were low in T cells derived from chronically virus-infected individuals compared to healthy subjects. Using CD4+ T cells treated with Top2α inhibitor or poisoner as a model, we demonstrated that Top2α inhibition disrupts the DNA topology, suppresses DNA repair kinase (ATM), and telomere protein (TRF2) expression, and induces T cell dysfunction. These findings reveal that Top2α inhibition is a mechanism by which viruses evade the host responses and establish persistent infection, and thus, restoring Top2α levels could be a way of boosting immune responses during chronic viral infections.
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Peng, Yanchun. "HLA-B51 associated HIV-1 viral control." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:8e06bed0-bd8d-4774-b137-c12f5e3547fc.
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Polymorphism in the Human Leucocyte Antigen (HLA) region of chromosome is the major source of host genetic variability in outcome of HIV-1 infection. However, there is limited understanding of the mechanisms underlying the beneficial effect of protective class I alleles such as HLA-B57, B27 and B51. Taking advantage of a unique cohort (SM cohort) infected with clade B’ HIV-1 through contaminated blood, in which many variables, such as the length of infection, the infecting viral strain and host genetic background are controlled, we performed a comprehensive study in order to understand HLA-B51 associated HIV-1 control. We first focused on the T cell responses against three dominant HLA-B51 restricted epitopes: GagNI9 (NANPDCKTI), Pol TV8 (TAFTIPSV) and Pol LI9 (LPPVVAKEI), and HLA-B51 associated escape mutations in these three epitopes. A sequential selection of epitope mutations (i.e., epitope Pol LI9, Pol TV8 and Gag NI9) was observed. Good control of viral load and higher CD4+ counts were significantly associated with at least one detectable T cell response to un-mutated epitopes. HLA-B51 restricted CD8+ T-cell clones, generated from the patients, could effectively inhibit HIV-1 replication when wild type epitopes are properly processed and presented. We then assessed the evolution of escape mutations under the selecting pressure of HLA-B51 CTLs in vitro by co-culturing HLA-B51 CTL clones with HIV-1 infected target cells (Virus Evolution Assay). Our data showed that three dominant HLA-B51 restricted CTL responses have driven the sequential escape mutations within the epitopes, leading to the loss of viral control, which confirmed our in vivo findings. Furthermore, applying Virus Evolution Assay, we assessed the impact of antigen sensitivity and TCR usage as well as founder virus effect on HIV-1 evolution and control. Our data suggested that antigen sensitivity plays an important role in anti-viral efficacy of CTLs; the TCR usage of CTLs has stronger effect on virus evolution. More importantly, our study highlighted the major impact of the founder virus sequence on viral control. It has been shown that HIV-1 has adapted to the T-cell responses to epitope Pol TI8 in other HLA-B51+ patient cohorts. However, in our cohort, T-cell responses targeting this epitope, with Valine at position 8 (Pol TV8), provide the hosts with a long-term protection against HIV-1 infection, because of a fine balance of efficient viral control, lower level of immune pressure and the slower rate of development of escape mutations. In addition, we assessed the ex vivo phenotypic characteristics of HLA-B51 restricted dominant T cell responses and our preliminary data indicated that the early differentiated and less senescence phenotype of CD8+ T cell responses in HIV-1 chronic infection is likely to be a result of low viral antigen exposure due to T cell driven escape. In conclusion, immune-dominant T-cell responses targeting three HLA-B51 restricted epitopes (Pol LI9, Pol TV8 and Gag NI9) could be advantageous for the host. In particular, the responses against epitope Gag NI9 with slow development of escape mutations or epitope Pol TV8 with a fine balance of moderate immune pressure and delayed escape mutations, are beneficial for long-term control of HIV-1 infection.
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Fernandez, Maria Helen. "The role of viral variation on CD4⺠T cell recognition in HIV-1." Thesis, University of London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325677.
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Williams, James Philip. "Characterisation of the HIV-1 reservoir and the potential for viral eradication." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:5ca5dd43-8045-47d9-a2b7-58713554e359.
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The HIV-1 reservoir is the major barrier to eradication and cure of HIV-1 infection. The aim of this thesis was to characterise the HIV-1 reservoir in PHI and to investigate two potential reservoir clearance strategies. Sensitive Q-PCR assays that quantify HIV-1 DNA reservoir level were developed and applied to characterise the HIV-1 reservoir in acutely infected patients enrolled in the SPARTAC trial. HIV-1 DNA levels were found to be a useful biomarker for predicting clinical progression and the time of viral remission in patients, after HAART interruption. Since low HIV-1 DNA reservoir levels were clinically beneficial, potential therapies aimed at decreasing the reservoir burden were investigated. Thermotherapy was employed as a possible method for increasing CTL killing ability of HIV-1-infected cells. This may increase the likelihood of virological control and functional cure. SPION uptake impacted negatively on the natural killing ability of CTL that expressed the high affinity 868-TCR. However, localised thermotherapeutic heat generation was insufficient to cause direct thermal ablation of bound target cells or to enhance the natural killing ability of CTL. 868-TCR transduced CTL were employed directly as a means to target the latent viral reservoir by the ‘kick and kill’ hypothesis. Latent HIV-1 was reactivated in a variety of latent cell line models, but inconclusively in a primary model. 868-TCR transduced CTL killing of latently infected cells was observed. However, reactivation of latent virus did not necessarily relate to increased antigenicity of latent cells, perhaps in part due to anti-latency drug-induced alterations in MHC class I expression. Despite recent and sustained interest in HIV-1 cure strategies, the prospect still remains elusive. Only through the development of sensitive assays that measure the HIV-1 reservoir and their application to novel and innovative cure strategies will HIV-1 ever be functionally cured or eradicated in patients on a large scale.
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Kishko, Michael G. "Molecular and Functional Properties of Transmitted HIV-1 Envelope Variants: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/519.
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In 2008 the Nobel Prize in Physiology or Medicine was awarded to the co-discoverers of the Human Immunodeficiency Virus Type 1 (HIV-1), the causative agent of Acquired Immunodeficiency Syndrome (AIDS). This award acknowledged the enormous worldwide impact of the HIV-1/AIDS pandemic and the importance of research aimed at halting its spread. Since the syndrome was first recognized, 25 million people have succumbed to AIDS and over 33 million are currently infected with HIV-1 (www.unaids.org). The most effective strategy for ending the pandemic is the creation of a prophylactic vaccine. Yet, to date, all efforts at HIV-1 vaccine design have met with very limited success. The consistent failures of vaccine candidates stem in large part from the unprecedented diversity of HIV-1.
Among the novel theories of vaccine design put forward to address this diversity is the targeted vaccine approach. This proposal is based on the finding that mucosal transmission of HIV-1, the most prevalent form, occurs across a selective bottleneck such that typically only a single (or a few) variants of the viral swarm present in a donor are passed to the recipient. While the mechanisms controlling the selection are largely unknown, the targeted vaccine approach postulates that once they are identified, we can utilize this understanding to design vaccines specifically targeted to the characteristics shared by the rare, mucosally transmissible HIV-1 variants.
The studies described in this work were conducted to improve our understanding of the factors influencing viral variant selection during mother-to-child-transmission of HIV-1, a route of mucosal transmission which has globally become the leading cause of child infection. A unique panel was generated, consisting of nearly 300 HIV-1 envelope genes cloned from infected mother-infant pairs. Extensive characterization of the genotypes, phenotypes and phylogeny of these clones was then done to identify attributes differentiating early infant from maternal variants. Low genetic diversity of HIV-1 envelope variants was detected in early infant samples, suggesting a bottleneck and active selection of variants for transmission. Transmitted variants did not differ from non-transmitted variants in CD4 and CCR5 use. Infant isolates replicated poorly in macrophages; a cell subtype hypothesized to be important in the establishment of infection. The sensitivity of infant envelope variants to neutralization by a panel of monoclonal antibodies, heterologous and autologous plasmas and HIV-1 entry inhibitors varied. Most intriguingly, envelopes cloned from infants infected during delivery exhibited a faster entry phenotype than maternal isolates. Together, these findings provide further insight into viral variant selection during mother-to-child transmission. Identification of properties shared by mucosally transmitted viral variants may allow them to be selectively targeted, resulting in improved methods for preventing HIV-1 transmission.
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Auma, Ann Winniefred Nangobi. "THE IMPACT OF DIRECT-ACTING ANTI-VIRAL THERAPY ON NAIVE CD4+ T CELL LYMPHOPENIA AND CELLULAR IMMUNE ACTIVATION IN HCV INFECTION AND HCV/HIV CO-INFECTION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1625764728651756.
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Ozen, Aysegul. "Structure and Dynamics of Viral Substrate Recognition and Drug Resistance: A Dissertation." eScholarship@UMMS, 2005. http://escholarship.umassmed.edu/gsbs_diss/677.
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Drug resistance is a major problem in quickly evolving diseases, including the human immunodeficiency (HIV) and hepatitis C viral (HCV) infections. The viral proteases (HIV protease and HCV NS3/4A protease) are primary drug targets. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition; the drug resistant protease variants are no longer effectively inhibited by the competitive drug molecules but can process the natural substrates with enough efficiency for viral survival. Therefore, the inhibitors that better mimic the natural substrate binding features should result in more robust inhibitors with flat drug resistance profiles. The native substrates adopt a consensus volume when bound to the enzyme, the substrate envelope. The most severe resistance mutations occur at protease residues that are contacted by the inhibitors outside the substrate envelope. To guide the design of robust inhibitors, we investigate the shared and varied properties of substrates with the protein dynamics taken into account to define the dynamic substrate envelope of both viral proteases. The NS3/4A dynamic substrate envelope is compared with inhibitors to detect the structural and dynamic basis of resistance mutation patterns. Comparative analyses of substrates and inhibitors result in a solid list of structural and dynamic features of substrates that are not shared by inhibitors. This study can help guiding the development of novel inhibitors by paying attention to the subtle differences between the binding properties of substrates versus inhibitors.
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Ozen, Aysegul. "Structure and Dynamics of Viral Substrate Recognition and Drug Resistance: A Dissertation." eScholarship@UMMS, 2013. https://escholarship.umassmed.edu/gsbs_diss/677.
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Drug resistance is a major problem in quickly evolving diseases, including the human immunodeficiency (HIV) and hepatitis C viral (HCV) infections. The viral proteases (HIV protease and HCV NS3/4A protease) are primary drug targets. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition; the drug resistant protease variants are no longer effectively inhibited by the competitive drug molecules but can process the natural substrates with enough efficiency for viral survival. Therefore, the inhibitors that better mimic the natural substrate binding features should result in more robust inhibitors with flat drug resistance profiles. The native substrates adopt a consensus volume when bound to the enzyme, the substrate envelope. The most severe resistance mutations occur at protease residues that are contacted by the inhibitors outside the substrate envelope. To guide the design of robust inhibitors, we investigate the shared and varied properties of substrates with the protein dynamics taken into account to define the dynamic substrate envelope of both viral proteases. The NS3/4A dynamic substrate envelope is compared with inhibitors to detect the structural and dynamic basis of resistance mutation patterns. Comparative analyses of substrates and inhibitors result in a solid list of structural and dynamic features of substrates that are not shared by inhibitors. This study can help guiding the development of novel inhibitors by paying attention to the subtle differences between the binding properties of substrates versus inhibitors.
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McCausland, Marie Rose. "Mucosal and Systemic Immune Phenotype is Altered During HIV-1 Infection and is Partially Restored and Further Disrupted in the Absence of Detectable Viral Replication." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1473679665919823.
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Huang, Kuan-Hsiang Gary. "The impact of host and therapy mediated selection on HIV-1 evolution." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:b49d0d79-75c9-4314-92ae-1f1789ac7d42.
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The Human immunodeficiency virus (HIV) pandemic has resulted in a heavy global disease burden, and clinically causes Acquired Immuno-Deficiency Syndrome (AIDS). The development of highly active antiretroviral therapy (HAART) has achieved remarkable control of the rapidly evolving HIV. However, HIV remains neither curable nor preventable by vaccine, and in the developing regions worst affected by HIV, HAART remains inaccessible to most patients. Furthermore, the change in both immunology and viral evolution during chronic HIV infection and its relation to AIDS pathogenesis remains unknown. Following the failure of recent HIV vaccines, it is believed that a better understanding of host-pathogen interaction is vital to advance therapeutic (vaccine and drug) design. In this thesis, I have performed an investigation of viral adaptation in response to different selection forces during advanced HIV infection and AIDS. The thesis first examined a case study that reveals the potential role of B cell-mediated neutralising antibody (NAb) in chronic HIV infection through the unexpected effect of B cell depletion agent, anti-CD20 (Rituximab). Here, longitudinal results have shown that viral load (VL), env gene diversity, and NAb sensitive strains increased during B cell and NAb depletion as a result of Rituximab administration, and reversed as B cells recovered. The study provides preliminary evidence to support the idea that NAb may be effective at suppressing HIV. The rest of the thesis focused on the cross-sectional cohort at Bloemfontein, South Africa (n=1491), a resource-limited region affected by the pandemic. Here, we used methods that include molecular and pretherapy drug resistance epidemiology, mathematical modelling, phylogenetically adjusted bioinformatics analysis and in vitro viral replication capacity (VRC) assay to study materials including cohort demography, plasma samples, CD4 cell count, VL, viral genetic sequences and host human leukocyte antigen (HLA) tissue types. Our analysis was further augmented by the additional data kindly contributed by our neighbouring Durban cohort collaborators (n=775), which also includes an IFN! ELISPOT assay that measures cytotoxic T lymphocyte (CTL) responses. Using the HIV pol sequencing data and phylogenetic analysis we confirmed that the local molecular epidemiology is similar to the circulating strains documented in the regional database. However, the pretherapy drug resistance mutation screening results have revealed an unexpected high incidence of drug-induced viral mutants in the AIDS patients with CD4 counts <100 cells/μl. According to mathematical modelling, this finding is attributable to additional sources of antiretroviral therapy exposure, which warrants public health caution. The investigation then focused on studying the changes in HLA class I mediated CTL selection and viral evolution as CD4 counts are reduced in AIDS. Interestingly we have noted evidence that suggest weakening CTL immune selection against gag during AIDS is associated with increased viral fitness (measured by VRC) and reversion of previous immune-escape mutations which conferred high fitness costs. In conclusion, this thesis compared different sources of host and drug mediated HIV selection and its implication for viral evolution. The identification of more bottleneck sites conferring high fitness costs to the selection of escape mutants is expected to be helpful in the design of future therapeutics (via vaccine, drug, immune therapy, or public health strategy). As we have learnt from the principle of combinational ARV, it would be desirable for a vaccine to select HIV at multiple sites of high escape-mutation fitness cost, hence offering protective effect.
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Brandano, Laura A. "Investigation of the C-Terminal Helix of HIV-1 Matrix: A Region Essential for Multiple Functions in the Viral Life Cycle: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/552.
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Since the first cases were reported over thirty years ago, great strides have been made to control disease progression in people living with HIV/AIDS. However, current estimates report that there are about 34 million individuals infected with HIV worldwide. Critical in the ongoing fight against this pandemic is the continuing development of highly active anti-retroviral therapies, ideally those with novel mechanisms of action. Currently, there are no medications approved for use that exploit the HIV-1 MA protein, despite its central role in multiple stages of the virus life cycle.
This thesis sought to examine whether a highly conserved glutamate residue at position 99 in the understudied C-terminal helix of MA is required for HIV-1 replication. I characterized a panel of mutant viruses that contain different amino acid substitutions at this position using viral infectivity studies, virus-cell fusion assays, and immunoblotting. In doing so, I found that substitution of this glutamate with either a valine (E99V) or lysine (E99K) residue disrupted Env incorporation into nascent HIV particles, and abrogated their ability to fuse with target-cell membranes. In determining that the strain of HIV could affect the magnitude of E99V-associated defects, I identified a compensatory substitution at MA residue 84 that rescued both E99V- and E99K-associated impairments.
I further characterized the MA E99V and E99K mutations by truncating HIV Env and pseudotyping with heterologous envelope proteins in an attempt to overcome the Env incorporation defect. Unexpectedly, I found that facilitating fusion at the plasma membrane was not sufficient to reverse the severe impairments in virus infectivity. Using quantitative PCR, I determined that an early post-entry step is disrupted in these particles that contain the E99V or E99K MA substitutions. However, allowing entry of mutant virus particles into cells through an endosomal route conferred a partial rescue in infectivity. As the characterization of this post-entry defect was limited by established virological methods, I designed a novel technique to analyze post-fusion events in retroviral infection. Thus, I present preliminary data regarding the development of a novel PCR-based assay that monitors trafficking of the viral reverse transcription complex (RTC) in an infected cell.
The data presented in this thesis indicate that a single residue in MA, E99, has a previously unsuspected and key role in multiple facets of HIV-1 MA function. The pleiotropic defects that arise from specific substitutions of this amino acid implicate a hydrophobic pocket in MA in Env incorporation and an early post-entry function of the protein. These findings suggest that this understudied region of MA could be an important target in the development of a novel antiretroviral therapy.
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Bandaranayake, Rajintha M. "Exploring Molecular Mechanisms of Drug Resistance in HIV-1 Protease through Biochemical and Biophysical Studies: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/487.
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The human immunodeficiency virus type-1 (HIV-1) is the leading cause of acquired immunodeficiency syndrome (AIDS) in the world. As there is no cure currently available to treat HIV-1 infections or AIDS, the major focus of drug development efforts has been to target viral replication in an effort to slow down the progression of the infection to AIDS. The aspartyl protease of HIV-1 is an important component in the viral replication cycle and thus, has been an important anti-HIV-1 drug target. Currently there are nine protease inhibitors (PIs) that are being used successfully as a part of highly active antiretroviral therapy (HAART). However, as is with all HIV-1 drug targets, the emergence of drug resistance substitutions within protease is a major obstacle in the use of PIs. Understanding how amino acid substitutions within protease confer drug resistance is key to develop new PIs that are not influenced by resistance mutations. Thus, the primary focus of my dissertation research was to understand the molecular basis for drug resistance caused by some of these resistance substitutions.
Until recently, the genetic diversity of the HIV-1 genome was not considered to be important in formulating treatment strategies. However, as the prevalence of HIV-1 continues, the variability of the HIV-1 genome has now been identified as an important factor in how the virus spreads as well as how fast the infection progresses to AIDS. Clinical studies have also revealed that the pathway to protease inhibitor resistance can vary between HIV-1 clades. Therefore, in studying the molecular basis of drug resistance in HIV-1 protease, I have also attempted to understand how genetic variability in HIV-1 protease contributes to PI resistance.
In Chapters II, III and Appendix 1, I have examined how clade specific amino acid variations within HIV-1 CRF01_AE and clade C protease affect enzyme structure and activity. Furthermore, I have examined how these sequence variations, which are predominantly outside the active site, contribute to inhibitor resistance in comparison to clade B protease. With the results presented in Chapter II, I was able to show that sequence variations within CRF01_AE protease resulted in structural changes within the protease that might influence enzyme activity. In Chapter III, I focused on how sequence variations in CRF01_AE influence protease activity and inhibitor binding in comparison to clade B protease. Enzyme kinetics data showed that the CRF01-AE had reduced catalytic turnover rates when compared to clade B protease. Binding data also indicated that CRF01_AE protease had an inherent weaker affinity for the PIs nelfinavir (NFV) and darunavir (DRV). In work described in Chapter III, I have also examined the different pathways to NFV resistance seen in CRF01_AE and clade B protease. Using x-ray crystallographic studies I have shown the molecular mechanism by which the two different pathways confer NFV resistance. Furthermore, I provide a rational for why different resistance pathways might emerge in the two clades. In Appendix I, I present results from a parallel study carried out on clade C protease.
In Chapter IV, I have examined the role of residue 50 in HIV-1 protease in modulating inhibitor binding. Patients failing amprevavir (APV) and DRV therapy often develop the I50V substitution while the I50L substitution is often observed in patients failing atazanavir (ATV) therapy. This indicates that by making subtle changes at residue 50 the protease is able to confer differential PI resistance. With binding data presented in this chapter I have shown that substitutions at residue 50 change the susceptibility profiles of APV, DRV and ATV. Furthermore, from analyses of protease-inhibitor complexes, I have described structural insights into how substitutions at residue 50 can modulate inhibitor binding.
This thesis presents results that reveal mechanistic insights into how a number of resistance substitutions within protease confer drug resistance. The results on non-B clade proteases demonstrate that clade specific sequence variations play a role in modulating enzyme activity and influence the pathway taken to confer PI resistance. Furthermore, the results provide structural insights into how amino acid substitutions outside the active site effectively alter inhibitor binding.
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Musich, Thomas A. "HIV-1 R5 Tropism: Determinants, Macrophages, and Dendritic Cells: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/599.
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Around thirty years ago HIV-1 was identified, and from that point the known epidemic has grown to over 30 million infected individuals. Early on in the course of HIV-1 research, viruses were classified as either syncytia inducing, CXCR4-using, T-cell tropic or non-syncytia inducing, CCR5-using, macrophage tropic. Since that time, several groups have shown that this is an oversimplification. There is a great deal of diversity amongst CCR5-using HIV-1 variants. There remains a great deal to be discovered regarding HIV-1 CCR5-tropism and how this affects other aspects of HIV-1 infection.
The CD4 binding site (CD4bs) on the HIV-1 envelope plays a major role in determining the capacity of R5 viruses to infect primary macrophages. Thus, envelope determinants within or proximal to the CD4bs have been shown to control the use of low CD4 levels on macrophages for infection. These residues affect the affinity for CD4 either directly or indirectly by altering the exposure of CD4 contact residues. In this thesis, a single amino acid determinant is described in the V1 loop that also modulates macrophage tropism. I identified an E153G substitution that conferred high levels of macrophage infectivity for several heterologous R5 envelopes, while the reciprocal G153E substitution abrogated infection. Shifts in macrophage tropism were associated with dramatic shifts in sensitivity to the V3 loop monoclonal antibody (MAb), 447-52D and soluble CD4, as well as more modest changes in sensitivity to the CD4bs MAb, b12. These observations are consistent with an altered conformation or exposure of the V3 loop that enables the envelope to use low CD4 levels for infection. The modest shifts in b12 sensitivity suggest that residue 153 impacts on the exposure of the CD4bs. However, the more intense shifts in sCD4 sensitivity suggest additional mechanisms that likely include an increased ability of the envelope to undergo conformational changes following binding to suboptimal levels of cell surface CD4. In summary, a conserved determinant in the V1 loop modulates the V3 loop to prime low CD4 use and macrophage infection.
In addition to determinants, this thesis seeks to evaluate the roles of macrophage tropic and non-macrophage tropic envelopes during the course of infection. Non-macrophage tropic virus predominates in immune tissue throughout infection, even in individuals suffering from HIV-associated dementia (HAD) who are known to carry many macrophage tropic viruses. There must be some advantage for these non-macrophage tropic viruses allowing them to persist in immune tissue throughout the disease. This thesis demonstrates that there is no advantage for these viruses to directly infect CD4+ T-cells, nor is there an advantage for them to be preferentially transmitted by dendritic cells to CD4+ T-cells. Given that transmitted/founder (T/F) viruses may preferentially interact with α4β7, and T/F viruses are non-macrophage tropic, I tested whether non-mac viruses could utilize α4β7 to their advantage. These experiments show that macrophage tropism does not play a role in gp120 interactions with α4β7. I evaluated whether there was a distinct disadvantage to macrophage tropic Envs, given their ability to infect dendritic cells and possibly stimulate the innate immune response. Using infected monocyte-derived dendritic cells (MDDCs), it was shown that mac-tropic Envs do not generate a significant immune response. These experiments demonstrate that there does not appear to be any advantage to non-macrophage tropic Envs, and that macrophage tropic Envs are able to infect CD4+ T-cells more efficiently, as well as DCs.
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Nelson, Patrick William. "Mathematical models of HIV pathogenesis and immunology /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/6783.
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James, Katherine Louise. "Viral genetics of HIV-2 infection." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:68ba022d-62e4-4cb1-8032-085ea5240b98.
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HIV-2 is a contemporary human retrovirus with the majority of infections localised to West Africa. Both HIV-1 and HIV-2 are able to cause AIDS; however, in contrast to HIV-1 infection, a common outcome following HIV-2 infection (∼ 37% of patients in this study cohort) is long-term non-progression (LTNP), where patients remain aviraemic and asymptomatic in the absence of treatment, often for decades. HIV-1 and HIV-2 both arose following zoonotic transmission of SIVs from non-human primates at around the beginning of the 20th century and when patients develop AIDS caused by HIV-2 infection, it is clinically indistinguishable from AIDS following HIV-1 infection. Whilst the estimated number of HIV-2 infections remains small in the context of the global HIV pandemic (HIV-2 ∼ 2 million, HIV-1 group M ∼75 million), the differences in pathogenicity between these two viruses has been a source of great interest, particularly the features of LTNPs that allow control of viral replication in the absence of anti-retroviral treatment. The studies described in this thesis were carried out using samples collected from a well-characterised longitudinal community cohort in Caió, Guinea-Bissau. Chapter 3 of this thesis presents an investigation into the variation and evolution present in the HIV-2 specific accessory gene vpx. The data showed significantly increased signals of positive selection pressure in vpx in viraemic when compared to non-viraemic patients and also allowed the identification of novel variations at high frequencies (up to 22%) in this cohort that were previously un-described. Chapters 4 and 5 present a novel application of shotgun RNA sequencing (RNA- Seq) to HIV ex vitro and ex vivo samples. Chapter 4 demonstrates the divergence seen in a cultured viral isolate at the level of the whole genome, in the absence of many of the biases typically involved in sequencing of RNA viruses. Chapter 5 further extends this method to show the applicability of using RNA-Seq on primary patient HIV samples for the first time. Analysis of diversity estimates over the whole genome in the context of a low bias sequencing method show a high level of diversity in HIV-2 pol and low diversity in vpx. The aim of this work was to combine traditional and novel sequencing methods to facilitate assessment of the variation and evolution acting on vpx and to generate an accurate picture of the genetic diversity over the whole genome of HIV-2.
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Brandin, Eleonor. "HIV-2 genetic evolution and viral dynamics." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-760-X/.
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Walther, Jallow Lilian. "Methods for detection of HIV-2/SIV infections /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4214-5/.
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Falconer, Karolin. "HIV-1/HCV co-infection immunity and viral dynamics /." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-762-7/.
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Long, Elizabeth Michelle. "Genetic and co-receptor characterization of viral diversity early in human immunodeficiency virus type 1 infection /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/4997.
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Zhang, Yuwen. "Equine innate and adaptive immunity to viral infections." Diss., Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/1013.
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Klingström, Jonas. "Hantaviruses : animal models, immunology and pathogenesis /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-071-0/.
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Lundholm, Peter. "Immune and autoimmune responses to HIV-1 in mucosa and other tissues /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3679-X/.
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Corrigan, Gary E. "Evaluation of reverse transcriptase assay for viral load monitoring /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-207-1/.
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García, Mark Megan Olga. "Production and validation of anti-HCV antibodies for viral neutralization." Thesis, KTH, Skolan för kemi, bioteknologi och hälsa (CBH), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-278578.
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Hepatitis-C Virus (HCV) remains the leading cause of liver transplant in the US and the UK, and the World Health Organization (WHO) estimates that 71 million people are infected worldwide. A vaccine would drastically impact the healthcare-associated burdens that HCV causes globally. The objective of this master’s thesis project is to produce human antibody (IgG) against HCV. This project will focus on the monoclonal antibodies (mAbs) HEPC3, AR3C, HEPC74, and HCV1. These four antibodies have been isolated from patients who have successfully cleared the infection, and their sequences and structures are available in the public domain. These four antibodies have also shown to bind to E2, a glycoprotein on the surface HCV that is crucial for viral binding and entry. This interaction of the mABs with E2 has been implicated in viral neutralization, making them promising choices for this study. Overall, 3 out of 4 mAbs were successfully cloned and produced. The unsuccessful antibody, HEPC74, was discovered to have failed due to an error in the plasmid sequence. Just as the western blot to confirm secretion was ready to be run, the laboratory closed due the Covid-19 outbreak. Therefore, the data can officially declare a ¾ mAb production success, however it is safe to assume that the alternative clone for HEPC74 was also a success due to a perfect sequence match. Since the primary objective of this project was to successfully clone and produce these four antibodies, then this study is considered an overall success. Lastly, this study examined how the same protocol could be applied the SARS-CoV-2 outbreak, by the cloning and production of anti-RBD IgG and testing them for viral neutralization.Hepatit-C (HCV) är fortsatt den enskilt största orsaken till levertransplantationer med uppskattningsvis 71 miljoner infekterade globalt sett, enligt världshälsoorganisationen (WHO).Ett vaccin mot HCV skulle drastiskt minska trycket på global hälso- och sjukvård. Syftet med detta projekt är att producera antikroppar (igG) mot HCV. Projektet fokuserar på HEPC3, AR3C, HEPC74 och HCV1 som är monoklonala antikroppar (mAbs). Dessa antikroppsvarianter har isolerats från patienter som tillfrisknat från infektion. Både DNA-sekvenser och strukturer av antikropparna finns offentligt tillgängliga. Dessa fyra antikroppar har också visats kunna binda till E2 som är ett membranbundet glykoprotein hos HCV som är centralt för viral adhesion och fusion. Interaktionen mellan dessa mAbs och E2 har visat sig neutralisera virulens, vilket gör dem till lovande kandidater för denna studie. Tre av fyra mAbs kunde klonas och produceras framgångsrikt. Försöket med HEPC74 misslyckades på grund av ett fel i plasmidsekvensen och just som western blot skulle genomföras för att bekräfta sekretion av en alternativ klon avslutades the praktiska arbetet med anledning av Covid-19 utbrottet. Resultaten visar entydigt att tre av fyra mAb producerades framgångsrikt. Det går dock att anta att det andra försöket med HEPC74 sannolikt också lyckades pga perfekt sekventiell matchning. Då det huvudsakliga syftet med projektet var att framgångsrikt klona och producera dessa fyra antikroppar så kan studien anses vara framgångsrik. Slutligen så undersöktes huruvida samma förfarande kunde appliceras mot SARS-CoV-2 genom kloning och produktion av anti-RBD IgG och tester av viral neutralisering.
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Pong, Chi-him, and 龐智謙. "HIV-1 Tat induced immune responses and its effect on opportunistic infections." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/207196.
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Acquired immunodeficiency syndrome (AIDS) is a major problem in our current society. There are over 35 million of the population that are currently living with human immunodeficiency virus (HIV), and the number of HIV-infected patients are still rising every year in spite of our efforts to control it. Furthermore, within the AIDS affected population, opportunistic infection is a major cause of complications and is the number one cause of death.
The HIV trans-activator (Tat) protein plays a major role in the AIDS pathogenesis. HIV-1 Tat is known to cause dysregulation of cytokines such as TNF-α, IL-6, and IL-10 in AIDS patients. In this study we recognized a proto-oncogene, c-Myc, could regulate the cytokine dysregulation caused by HIV-1 Tat in primary blood monocyte derived macrophages (PBMac). By knocking down the expression of c-Myc with gene specific small-interfering RNA (siRNA), we demonstrated that c-Myc may be critical for the expression of the pro-inflammatory cytokines TNF-α and IL-6. HIV-1 Tat was subsequently found to regulate the expression of c-Myc via the activation of dsRNA-activated protein kinase (PKR), ERK1/2 and p38 mitogen-activated protein kinase (MAPK). Furthermore, c-Myc regulation of the pro-inflammatory cytokines was demonstrated to have a role in AIDS related opportunistic infections. HIV-1 Tat was shown to increase the intracellular growth of Mycobacteria avium complex (MAC) within PBMac. This increase in MAC growth was in turn found to be regulated by TNF-α expression controlled by c-Myc.
HIV-1 Tat was also demonstrated to induce the expression of RIG-I, a common pattern recognition receptor of double stranded RNA viruses, in PBMac. RIG-I is known to activate the viral immune responses such as the type-I interferon (IFN) and pro-inflammatory cytokine pathways. This induction of RIG-I by HIV-1 Tat was found to be regulated by c-Myc, as well as through other signalling kinases such as p38 MAPK and PKR. Tat induction of RIG-I ultimately led to the induction of IFN-α2 and IFN-β through the expression and nuclear translocation of the interferon regulatory factor-7 (IRF-7). This alteration in type-I IFN expression regulated by HIV-1 Tat and RIG-I was also found to play a role against AIDS related opportunistic infections. HIV-1 Tat is known to increase the infectivity of Kaposi’s sarcoma-related herpesvirus (KSHV), a common opportunistic viral infection. We were able to demonstrate that this increase in KSHV infectivity was regulated by RIG-I and type-I IFN induced by HIV-1 Tat.
Lastly, this study also demonstrated how HIV-1 Tat was able to manipulate the expression of IL-8 induced by KSHV in PBMac. HIV-1 Tat was able to mediate the production of IL-8 induced by KSHV by altering the phosphorylation of the p38 MAPK and the signal transducer and activator of transcription-1 (STAT-1).
Taken together, the results of this study showed how c-Myc and RIG-I may be able to play critical roles in HIV-1 Tat induced cytokine dysregulation. Furthermore, the importance of these pathways is further demonstrated in their roles in regulating the immune responses against opportunistic infections in AIDS patients.published_or_final_version
Paediatrics and Adolescent Medicine
Doctoral
Doctor of Philosophy
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區建兒 and Kin-yi Au. "HIV Tat and mycobacteria-induced innate immune responses." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/193389.
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Acquired Immunodeficiency Syndrome (AIDS) and tuberculosis (TB) have posed diagnostic and therapeutic challenges globally. Nowadays, it is estimated that 34 millions people are living with Human Immunodeficiency Virus (HIV). About 2 millions of people die from AIDS-related causes currently in each year. Tuberculosis is the most common presenting illness and leading cause of death among AIDS patients. Emerging studies suggest that HIV and Mycobacterium tuberculosis (Mtb), the causative pathogen of TB, act synergistically to accelerate decline of immune functions and cause the death.
Mtb infection usually remains latent. Only small portion of infected individuals develops active TB. However HIV infection boosts the risk of reactivation of TB and susceptibility to new Mtb infection. In contrast, Mtb infection dysregulates cytokines production and induces HIV viral replication. Although it is well-known that HIV and Mtb potentiate each other in disease development, mechanisms of interaction of the two pathogens remain not well-elucidated. The aim of this study is to investigate the interaction of HIV viral protein Tat with mycobacteria infection, which may provide insights in the interplay between HIV and Mtb infections.
HIV viral transactivator protein, Tat, plays a critical role in HIV replication; and its induction of apoptosis in CD4+ T cells contributes to immune defects. In this study, Tat was demonstrated to dysregulate immune responses against mycobacteria such as autophagy, a tightly regulated bacterial clearance mechanism. With pretreatment of the primary human blood monocyte-derived macrophages with Tat, the interferon-γ (IFN-γ)-induced Signal Transducer and Activator of Transcription-1 (STAT-1) phosphorylation was suppressed. Inhibition of STAT-1 phosphorylation ultimately led to downregulation of autophagy-associated gene, microtubule-associated protein light chain 3 (LC3) expressions. Of note, Tat was demonstrated to inhibit the colocalization of Bacillus Calmette Guerin (BCG) and IFN-γ-induced autophagosomes under fluorescent microscopy examination.
In addition to the inhibition of bactericidal autophagy, Tat was found to manipulate cytokines production. Tat was demonstrated to enhance mycobacteria-induced tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) production. TNF-α and IL-1β have been well-demonstrated in literatures that can limit bacterial growth. They, however, have been also shown as important contributors to the increase of HIV viral replication in HIV and mycobacteria coinfection. Mtb-induced TNF-α production can induce transcriptional activation of the HIV long terminal repeat (LTR) promoter while blocking of IL-1β production decreases HIV replication. Tat enhancement of these cytokines production may therefore contribute to the knowledge of the increased viral replication in HIV and mycobacteria coinfection.
Furthermore, new microRNAs, up-and-coming fine-tuners of innate immunity, were discovered. MicroRNAs, a family of non-coding RNAs, can regulate gene expressions post-transcriptionally and control various developmental and cellular processes. They can target mRNAs of cellular signaling molecules, transcription factors or cytokines as to regulate the immunity. Herein, microRNA-1303, originally with unknown function, was shown to regulate mycobacteria-induced TNF-α production and affect the Tat enhancement of TNF-α production.
Taken together, the results of this study demonstrated that HIV viral protein, Tat could dysregulate immune responses to mycobacteria. The study of the dysregulation may further elucidate the interplay between HIV and mycobacteria infections.published_or_final_version
Paediatrics and Adolescent Medicine
Doctoral
Doctor of Philosophy
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Hsu, Pao-Chu. "Prenatal Stress, Depression, and Herpes Viral Titers." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4818.
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Recent studies suggest that some cases of prenatal depression may be associated with reactivation of latent infections of the herpesvirus family. The possible relationships among stress, prenatal depression, and herpes viral reactivation in pregnancy are understudied and the molecular pathways such as the neuroimmune biogenic amine pathway are unidentified. Chronic stress shifts the T helper-1 cell (Th1) cytokine profile to a Th2 profile, which favors virus induced pathogenesis and survival. Pregnancy is also associated with a similar Th2 dominance. In non-pregnant individuals, exposure to psychological or physical stress may be associated with latent herpes viral reactivation and could result in behavioral deficits and depression. Normally, type-1 cytokines such as Interferon-gamma (IFN -gamma) and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) induce indoleamine-2, 3-dioxygenase (IDO) activation which inhibits herpes virus replication and reactivation, decreases tryptophan production, and alters phenylalanine /tyrosine metabolism. Thus it is possible that prenatal depression may occur from tryptophan stealing through the IDO pathway which results in decreased serotonin as well as increased risk for latent herpes viral reactivation.
The purpose of this study is to analyze the relationships among stress, herpes viral titers, depression, and metabolites of IDO activation, which involves tryptophan and guanosine-triphosphate-cyclohydrolase-1(GTP-CH1) pathways. This study builds on Influence of Lactation on Postpartum Stress and Immunity (Grant number: R01-NR05000) which investigated perinatal immune, endocrine, and inflammatory changes in pregnancy and the postpartum. A secondary data analysis was conducted on baseline data from women collected at 16 to 25 gestational weeks. This data set included some herpes viral titers, and additional ones were measured in stored plasma samples. The aim of this study is to examine relationships among stress, herpes viral reactivation, depression, and the IDO activation pathway. The results of this study provide information about the possible role of further relationships of prenatal stress, latent herpes viral reactivation, and depression mechanisms. The results will be important in health promotion and disease prevention during pregnancy.
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Mowafi, Frida. "Chemokines and chemokine receptors during viral infections in man /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-420-4/.
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Silverstein, Noah J. "Disease Tolerance, Epigenetic Inheritance, and Surviving Pathogenic Viral Infections." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1149.
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Health is often defined in terms of absence of disease or pathological processes, but this is a definition of exclusion and incomplete. For example, SARS-CoV-2 viral load does not reliably predict disease severity, and so individuals must vary in their ability to control inflammation and maintain normal tissue homeostasis. This host defense strategy is called disease tolerance, and better understanding of disease tolerance mechanisms could change the way that we treat disease and work to maintain health.
The first project presented in this dissertation found that after accounting for effects of age and sex, innate lymphoid cells (ILCs), but not T cells, were lower in adults and children sick with COVID-19 or MIS-C, independent of lymphopenia. Furthermore, abundance of ILCs, but not of T cells, correlated inversely with disease severity. These blood ILCs were shown to produce amphiregulin, a protein implicated in disease tolerance and tissue homeostasis, and the percentage of amphiregulin-producing ILCs was lower in males. These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance accounts for increased COVID-19 severity with age and in males.
The second project describes a novel mouse model of epigenetic inheritance wherein paternal influenza A virus (IAV) infection results in less severe influenza disease in IAV infected offspring. This offspring phenotype was not attributable to differences in viral load, indicating a possible difference in disease tolerance. Paternal caloric deprivation decreased, and influenza B virus infection increased, offspring influenza disease severity, and in vitro fertilization demonstrated sperm are sufficient to transfer IAV-associated epigenetic inheritance phenotypes.
These findings represent a foundation for further work that, by continuing to elucidate the mechanisms of disease tolerance and epigenetic inheritance, could provide novel therapeutic interventions to help promote and maintain health.
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Boyd, Anders. "Clinical epidemiology of multi-viral hepatitis infection among HIV-HBV infected patients." Paris 6, 2010. http://www.theses.fr/2010PA066618.
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Ces dix dernières années, l'allongement de l'espérance de vie des patients infectés par le VIH s'est accompagné de l'apparition de co-morbidités, en particulier hépatiques, dues aux co-infections chroniques par les virus des hépatites B (VHB), C (VHC) et Delta (VHD). Alors que les patients co-infectés par le VIH-VHB sont plus à risque d'être infectés par d'autres virus des hépatites chroniques, les données concernant spécifiquement l'influence respective des co-infections VHC, VHD et VHC-VHD sur les conséquences cliniques, le suivi virologique et l'efficacité du traitement dans le contexte du VIH sont quasi-inexistantes. A l'occasion de ce travail de thèse, nous avons montré dans un premier temps que l'hépatite Delta était un facteur prédictif majeur de fibrose et cirrhose par rapport aux patients co-infecté par le VIH-VHB ou VIH-VHB-VHC. Ensuite, nous avons montré que l'infection par le VHD est associée par une suppression de la réplication du VHB et VHC, même en présence d'un traitement antiviral efficace. Cependant, la persistance de blips de charge virale suggère qu'il est indispensable de mettre en place un suivi virologique rapproché des patients porteurs de co-infections multiples. Enfin, nous avons montré que le ténofovir, un des traitements majeurs contre le VHB, influence l'évolution de la fibrose chez les patients co-infectés VIH-VHB, mais pas chez les patients porteurs du VHD. Toutes ces données portant principalement sur l'hépatite Delta ont permis d'étayer l'impact clinique, virologique et thérapeutique de cette infection et d'apporter ainsi des éléments pour guider les recommandations de prise en charge de ces pathologies.
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Larsson, Anna-Karin. "Early life cytokines, viral infections and IgE-mediated allergic disease." Doctoral thesis, Stockholm : Wenner-Gren Institute for Experimental Biology, Stockholm university, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-1224.
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Zhao, Juan. "Role of ATM in T Cell Dysfunction During Chronic Viral Infections." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etd/3531.
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Hepatitis C virus (HCV) or human immunodeficiency virus (HIV) infection leads to a phenomenon of inflammaging, in which chronic infection or inflammation induces an immune aged phenotype with T cell dysfunction. Thus, HCV or HIV infection has been deemed as a model to study the mechanisms of T cell infammaging and viral persistence in humans. In this dissertation, T cell homeostasis, DNA damage and repair machineries were investigated in patients with chronic HCV or HIV infection at risk for inflammaging. We found a significant depletion in CD4 T cells, which was correlated with their apoptosis in chronically HCV/HIVinfected patients, compared to age-matched healthy subjects. In addition, virus-infected patients’ CD4 T cells were prone to DNA damage that extended to chromosome ends (telomeres), leading to accelerated telomere erosion - a hallmark of senescence. Mechanistically, the DNA doublestrand break (DSB) sensor MRE11, RAD50, and NBS1 (MRN) remained intact, but the DNA damage checkpoint kinase ataxia telangiectasia mutated (ATM) and its downstream checkpoint kinase 2 (CHK2) were significantly suppressed in T cells from HCV/HIV-infected individuals. Consistently, ATM/CHK2 activation, DNA repair, and cellular functions were also impaired in primary CD4 T cells following ATM knockdown, or exposure to the ATM inhibitor (KU60019), as well as in CD4 T cells co-cultured with HCV-infected hepatocytes, or a T cell line infected with HIV-1 in the presence of raltegravir in vitro, which recapitulates the biological effects observed in T cells in the setting of HCV/HIV infection in vivo. Importantly, ectopic expression of ATM was essential and sufficient to reduce the DNA damage, survival deficit, and cellular dysfunction in T cells from both HCV and HIV-infected individuals. These results demonstrate that failure of DSB repair due to ATM deficiency leads to unrepaired DNA damage and renders virally infected patients’ T cells prone to senescence and apoptosis, thus contributing to CD4 T cell loss or dysfunction during chronic HCV or HIV infection. This study reveals a novel mechanism by which ATM deficiency promotes telomeric DNA damage and premature T cell aging, and provides a new therapeutic target for inflammaging-induced immune dysfunction during chronic viral infection.
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Kjerrström, Zuber Anne. "Enhancement of HIV-1 DNA immunogens /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-304-x.
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Roberts, Hannah E. "Modelling HIV dynamics and evolution : prospects for viral control." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:1e2c153f-bd52-4da2-a1d2-47008687fd09.
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The human immunodeficiency virus (HIV) epidemic is far from over. Antiretroviral therapy (ART) is effective at suppressing viral replication within a patient but it must be taken daily and is life-long. Therefore, the development of a therapy that could induce drug-free remission or constitute a functional cure is a key focus of HIV research. In this thesis I explore three mechanisms which could lead to more individuals being able to control their viraemia in the absence of ART: (1) T-cell immunity, (2) early initiation of ART, and (3) viral evolution. Firstly, a strong HIV-specific T-cell response has been linked to rare cases of spontaneous viral control, but the extent to which this arm of the immune response contributes to viral control is debated. Several types of data are used to answer this question, including the rate at which the virus evolves to escape the CD8+ T-cell response. I study the frequency of incident immune escape in the largest cohort used for this purpose to date. Secondly, some patients, with characteristics dissimilar to spontaneous HIV controllers, are able to control the virus for years after the interruption of ART that was initiated early in infection. I use mathematical models to investigate a new hypothesis for the differing outcomes of early- and late- initiated ART. Thirdly, since HIV is a relatively new infection of humans it is still adapting to its new host. Recent studies suggest that the virus could be evolving towards decreased virulence at the population level. I study whether the widespread administration of ART has the potential to alter the course of virulence evolution and might result in a further attenuated virus. I conclude by discussing the implications of these results for viral control at the individual level and also for population level epidemic control.
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Nowak, Piotr. "Aspects of immune activation in HIV-1 infection /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-190-6/.
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Pyakurel, Pawan. "AIDS and endemic kaposi's sarcoma development comparison by histopathology, virology (HHV-8/KSHV) and cytogenetics /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-465-1/.
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Peretz, Yoav. "Long term non progressors : clues for defining immune correlates of protection from HIV disease progression." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111898.
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Throughout history, human populations have continuously been challenged by new and emerging infectious diseases. For the past 26 years, sub-Saharan Africa and other countries around the world have been dealing with a pandemic caused by a relatively new pathogen called the human immunodeficiency virus (HIV). Although antiretroviral (ARV) therapies effectively reduce morbidity and mortality rates, the long term use in those who have access to treatment inevitably leads to drug-related toxicity and resistance. Even with a strong commitment from governments to expand and finance prevention and treatment programs, transmission rates continue to outpace the benefits of these efforts. Therefore to effectively eradicate the disease, research is focusing on the design of protective and therapeutic vaccines. The first major step in designing these alternative therapies is to define correlates of immune protection.The research presented in this thesis focuses on characterizing the quantitative and qualitative features of T cell immune responses in individuals who spontaneously control viral replication and exhibit a benign course of disease while remaining off ARV therapy. A comprehensive analysis of HIV-specific IFN-gamma secreting immune responses revealed that neither the breadth nor the magnitude of responses directed against the entire HIV proteome accurately predicts the viral load or rate of CD4 decline. Subsequent analyses showed that the preferential targeting of Gag was associated with reduced rates of CD4 decline and was later confirmed in a cohort of individuals in primary infection whereby the relative breadth and magnitude of Gag p24 was inversely correlated with viral load set point.
The maintenance of polyfunctional immune responses in HIV-infected subjects with a benign course of disease prompted us to develop a method that could comprehensively assess the breadth, magnitude and specificity of three functionally distinct subsets of HIV-specific lymphocytes (single IFN-gamma, single IL-2 and dual IFN-gamma/IL-2 secretors). Survey of immune responses in chronically infected individuals revealed that only the breadth and magnitude of dual IFN-gamma/IL-2 secreting lymphocytes correlated with reduced viral loads and increased CD4 counts suggesting that secretion of IFN-gamma alone was a poor correlate of protection. We also showed that the contribution of polyfunctional lymphocytes to the total response was greater for epitopes restricted by major histocompatibility complex (MHC) class I alleles associated with slow disease progression compared to those restricted by alleles associated with rapid or neutral rates of HIV disease progression.
Taken together, this work supports the view that immune monitoring of infected and vaccinated individuals should include methodologies capable of detecting both IFN-gamma and IL-2 secretion from responding T lymphocytes. The studies presented here have furthered our understanding of what constitutes protection from disease progression emphasizing that both specificity and polyfunctionality are features of effective control of viral replication.
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Che, Jenny Wun-Yue. "Heterologous Immunity and T Cell Stability During Viral Infections: A Dissertation." eScholarship@UMMS, 2002. http://escholarship.umassmed.edu/gsbs_diss/697.
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The immune response to an infection is determined by a number of factors, which also affect the generation of memory T cells afterwards. The immune response can also affect the stability of the pre-existing memory populations. The memory developed after an infection can influence the response to subsequent infections with unrelated pathogens. This heterologous immunity may deviate the course of disease and alter the disease outcome. The generation and stability of memory CD8 T cells and the influence of the history of infections on subsequent heterologous infections are studied in this thesis using different viral infection sequences.
Previous studies using mice lacking individual immunoproteasome catalytic subunits showed only modest alterations in the CD8 T cell response to lymphocytic choriomeningitis virus (LCMV). In this study, I found that the CD8 T cell response to LCMV was severely impaired in mice lacking all three catalytic subunits of the immunoproteasome, altering the immunodominance hierarchy of the CD8 T cell response and CD8 T cell memory. Adoptive transfer experiments suggested that both inefficient antigen presentation and altered T cell repertoire contribute to the reduction of the CD8 T cell response in the immunoproteasome knockout mice.
Immune responses generated during infections can reduce pre-existing memory T cell populations. Memory CD8 T cells have been shown to be reduced by subsequent heterologous infections. In this study, I re-examined the phenomenon using immune mice infected with LCMV, murine cytomegalovirus (MCMV) and vaccinia virus (VACV) in different infection sequences. I confirmed that memory CD8 T cells were reduced by heterologous infections, and showed that LCMV-specific memory CD4 T cells were also reduced by heterologous infections. Reduction of the memory CD8 T cells is thought to be the result of apoptosis of memory CD8 T cells associated with the peak of type I interferon early during infection. I showed that memory CD4 T cells were similarly driven to apoptosis early during infection; however, Foxp3+ CD4+ regulatory T cells were relatively resistant to virus infection-induced apoptosis, and were stably maintained during LCMV infection. The stability of Treg cells during viral infections may explain the relatively low incidence of autoimmunity associated with infections.
The history of infections can deviate the course of disease and affect the disease outcome, but this heterologous immunity is not necessarily reciprocal. Previous studies have shown the effects of heterologous immunity during acute infections. In this thesis, I showed that the history of LCMV infection led to higher viral titers during persistent MCMV infection, caused more severe immunopathology at the beginning of infection, and reduced the number of MCMV-specific inflationary memory CD8 T cells after the period of memory inflation. In a different context of infection, the history of LCMV infection can be beneficial. LCMV-immune mice have been shown to have lower viral titers after VACV infection, but VACV-immune mice are not protected during LCMV infection. I found that memory CD8 T cells generated from LCMV and VACV infections were phenotypically different, but the differences could not explain the nonreciprocity of heterologous immunoprotection. By increasing the number of crossreactive VACV A11R198-205-specific memory CD8 T cells, however, I showed that some VACV-immune mice displayed reduced viral titers upon LCMV challenge, suggesting that the low number of potentially cross-reactive CD8 T cells in VACV-immune mice may be part of the reasons for the non-reciprocity of immunoprotection between LCMV and VACV. Further analysis deduced that both number of potentially cross-reactive memory CD8 T cells and the private specificity of memory CD8 T cell repertoire played a part in determining the outcome of heterologous infections.
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Che, Jenny Wun-Yue. "Heterologous Immunity and T Cell Stability During Viral Infections: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/697.
Full textAbstract:
The immune response to an infection is determined by a number of factors, which also affect the generation of memory T cells afterwards. The immune response can also affect the stability of the pre-existing memory populations. The memory developed after an infection can influence the response to subsequent infections with unrelated pathogens. This heterologous immunity may deviate the course of disease and alter the disease outcome. The generation and stability of memory CD8 T cells and the influence of the history of infections on subsequent heterologous infections are studied in this thesis using different viral infection sequences.
Previous studies using mice lacking individual immunoproteasome catalytic subunits showed only modest alterations in the CD8 T cell response to lymphocytic choriomeningitis virus (LCMV). In this study, I found that the CD8 T cell response to LCMV was severely impaired in mice lacking all three catalytic subunits of the immunoproteasome, altering the immunodominance hierarchy of the CD8 T cell response and CD8 T cell memory. Adoptive transfer experiments suggested that both inefficient antigen presentation and altered T cell repertoire contribute to the reduction of the CD8 T cell response in the immunoproteasome knockout mice.
Immune responses generated during infections can reduce pre-existing memory T cell populations. Memory CD8 T cells have been shown to be reduced by subsequent heterologous infections. In this study, I re-examined the phenomenon using immune mice infected with LCMV, murine cytomegalovirus (MCMV) and vaccinia virus (VACV) in different infection sequences. I confirmed that memory CD8 T cells were reduced by heterologous infections, and showed that LCMV-specific memory CD4 T cells were also reduced by heterologous infections. Reduction of the memory CD8 T cells is thought to be the result of apoptosis of memory CD8 T cells associated with the peak of type I interferon early during infection. I showed that memory CD4 T cells were similarly driven to apoptosis early during infection; however, Foxp3+ CD4+ regulatory T cells were relatively resistant to virus infection-induced apoptosis, and were stably maintained during LCMV infection. The stability of Treg cells during viral infections may explain the relatively low incidence of autoimmunity associated with infections.
The history of infections can deviate the course of disease and affect the disease outcome, but this heterologous immunity is not necessarily reciprocal. Previous studies have shown the effects of heterologous immunity during acute infections. In this thesis, I showed that the history of LCMV infection led to higher viral titers during persistent MCMV infection, caused more severe immunopathology at the beginning of infection, and reduced the number of MCMV-specific inflationary memory CD8 T cells after the period of memory inflation. In a different context of infection, the history of LCMV infection can be beneficial. LCMV-immune mice have been shown to have lower viral titers after VACV infection, but VACV-immune mice are not protected during LCMV infection. I found that memory CD8 T cells generated from LCMV and VACV infections were phenotypically different, but the differences could not explain the nonreciprocity of heterologous immunoprotection. By increasing the number of crossreactive VACV A11R198-205-specific memory CD8 T cells, however, I showed that some VACV-immune mice displayed reduced viral titers upon LCMV challenge, suggesting that the low number of potentially cross-reactive CD8 T cells in VACV-immune mice may be part of the reasons for the non-reciprocity of immunoprotection between LCMV and VACV. Further analysis deduced that both number of potentially cross-reactive memory CD8 T cells and the private specificity of memory CD8 T cell repertoire played a part in determining the outcome of heterologous infections.
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Navér, Lars. "Perinatal HIV-1 infection : aspects on clinical presentation, viral dynamics and epidemiology /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-983-8/.
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Eriksson, Lars E. "HIV therapies : from health-related quality of life to DNA levels /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-519-0/.
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Wright, Alison Laing. "IGA MEDIATED DEFENSES AGAINST HIV-1." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1201290332.
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Benki, Sarah Frances. "The relationship between female reproductive hormones and HIV-1 /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/11517.
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Svedhem, Johansson Veronica. "Kinetics of HIV-1 drug resistance mutations in vivo /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-671-9/.
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Truong, Hong-Ha Manh. "Molecular epidemiology of HIV-1 transmission : a case study of source partners of individuals with acute retroviral syndrome /." Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/9282.
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Cragg, Carol Diane. "Evaluating viral load monitoring in antiretroviral-experienced HIV-positive pregnant women accessing antenatal care in Khayelitsha, Cape Town." Master's thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/16490.
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Includes bibliographical referencesBACKGROUND: A viral load monitoring algorithm in the 2013 Western Cape Department of Health PMTCT guidelines include VL measurement in women who are antiretroviral (ART)-experienced at presentation for antenatal care, the timing of subsequent VL measurements and criteria for regimen change. The study evaluates the implementation of the algorithm in women who are virologically nonsuppressed and determines the outcomes of virological resuppression and infant PCR status. METHODS: This retrospective cohort study focused on all ART-experienced women who presented for antenatal care at one of two primary level Maternity Obstetric Units (MOUs) in Khayelitsha, Cape Town between July 2013 and June 2014. The study used routine data from facility registers, clinical records and electronic monitoring systems at the MOU, and referral ART sites and hospitals. Data collected included age, ART clinic, start date and regimen, and maternal VL and infant PCR results. RESULTS: Forty percent of the 1412 HIV-positive pregnant women, were ART-experienced, of whom 14.1 % were VNS. Predictors of being VNS included a duration on ART of more than 4 years (p= 0.04), attending an ART clinic other than that in the facility (p= 0.02), being on a second-line ART regimen (p=0.07) and being younger than 25 years (p= 0.05). The algorithm was correctly followed in up to 87.5% of women identified as VNS. The rate of virological resuppression by three months postpartum was 70.0% to 82.3%. Excluding three neonates who died, all of the 82.2% of infants tested were PCR negative. CONCLUSIONS: Nearly 15% of ART-experienced women were virologically nonsuppressed on presentation for antenatal care. Levels of adherence to the guideline, and virological resuppression rates of up to 82.3% are encouraging. The implementation of the VLM algorithm could be improved by the integration of obstetric and ART care, the adoption of a single electronic monitoring system and the use of standardised integrated clinical stationery.
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Lazaryan, Aleksandr. "Human leukocyte antigen supertypes in relation to human imunodeficiency virus infection among populations of African ancestry." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2009r/lazaryan.pdf.
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