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Nikin-Beers, Ryan Patrick. "Immunoepidemiological Modeling of Dengue Viral Infection." Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/82924.
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Dengue viral infection is a mosquito-borne disease with four distinct strains, where the interactions between these strains have implications on the severity of the disease outcomes. The two competing hypotheses for the increased severity during secondary infections are antibody dependent enhancement and original antigenic sin. Antibody dependent enhancement suggests that long-lived antibodies from primary infection remain during secondary infection but do not neutralize the virus. Original antigenic sin proposes that T cells specific to primary infection dominate cellular immune responses during secondary infections, but are inefficient at clearing cells infected with non-specific strains.
To analyze these hypotheses, we developed within-host mathematical models. In previous work, we predicted a decreased non-neutralizing antibody effect during secondary infection. Since this effect accounts for decreased viral clearance and the virus is in quasi-equilibrium with infected cells, we could be accounting for reduced cell killing and the original antigenic sin hypothesis.
To further understand these interactions, we develop a model of T cell responses to primary and secondary dengue virus infections that considers the effect of T cell cross-reactivity in disease enhancement. We fit the models to published patient data and show that the overall infected cell killing is similar in dengue heterologous infections, resulting in dengue fever and dengue hemorrhagic fever. The contribution to overall killing, however, is dominated by non-specific T cell responses during the majority of secondary dengue hemorrhagic fever cases. By contrast, more than half of secondary dengue fever cases have predominant strain-specific T cell responses. These results support the hypothesis that cross-reactive T cell responses occur mainly during severe disease cases of heterologous dengue virus infections.
Finally, using the results from our within-host models, we develop a multiscale model of dengue viral infection which couples the within-host virus dynamics to the population level dynamics through a system of partial differential equations. We analytically determine the relationship between the model parameters and the characteristics of the solutions, and find thresholds under which infections persist in the population. Furthermore, we develop and implement a full numerical scheme for our model.<br>Ph. D.
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Nikin-Beers, Ryan Patrick. "Mathematical Modeling of Dengue Viral Infection." Thesis, Virginia Tech, 2014. http://hdl.handle.net/10919/48594.
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In recent years, dengue viral infection has become one of the most widely-spread mosquito-borne diseases in the world, with an estimated 50-100 million cases annually, resulting in 500,000 hospitalizations. Due to the nature of the immune response to each of the four serotypes of dengue virus, secondary infections of dengue put patients at higher risk for more severe infection as opposed to primary infections. The current hypothesis for this phenomenon is antibody-dependent enhancement, where strain-specific antibodies from the primary infection enhance infection by a heterologous serotype. To determine the mechanisms responsible for the increase in disease severity, we develop mathematical models of within-host virus-cell interaction, epidemiological models of virus transmission, and a combination of the within-host and between-host models. The main results of this thesis focus on the within-host model. We model the effects of antibody responses against primary and secondary virus strains. We find that secondary infections lead to a reduction of virus removal. This is slightly different than the current antibody-dependent enhancement hypothesis, which suggests that the rate of virus infectivity is higher during secondary infections due to antibody failure to neutralize the virus. We use the results from the within-host model in an epidemiological multi-scale model. We start by constructing a two-strain SIR model and vary the parameters to account for the effect of antibody-dependent enhancement.<br>Master of Science
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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 20<sup>th</sup> 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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Pruikkonen, H. (Hannele). "Viral infection induced respiratory distress in childhood." Doctoral thesis, Oulun yliopisto, 2015. http://urn.fi/urn:isbn:9789526207919.
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Abstract Dyspnoea associated with respiratory infection is a common symptom in infancy and early childhood. Inspiratory stridor is the main symptom in cases of croup and expiratory wheezing in cases of bronchiolitis, obstructive bronchitis and acute asthma exacerbations. Dyspnoea associated with respiratory infection is a common cause of emergency department visits and unplanned hospital admissions among infants and preschool children. The assessment of dyspnea associated with acute childhood respiratory infection is largely subjective, and evidence regarding the severity of acute dyspnoea is needed in order to target hospital admissions more accurately. Wheezing associated with respiratory infection in infancy has been recognized as an important predictor of recurrent wheezing and asthma at school age. The aims of this study were to determine the risk factors for croup, to evaluate factors that reliably predict the need for hospitalizing children with acute wheezing and to find out whether respiratory infection with wheezing during infancy has a positive association with the development of asthma during childhood. The work included two register-based surveys and one prospective cohort study. It is concluded that a family history of croup is an exceptionally strong risk factor for croup and its recurrence in childhood. The early phase of bronchiolitis is unstable in infants below 6 months of age. These infants are most likely to need medical interventions in the first 5 days after onset of the disease. A positive respiratory syncytial -virus test result, a fever of more than 38°C and low initial oxygen saturation are predictors of the need for hospitalization and medical interventions. An initial oxygen saturation >93% effectively identifies children aged more than 6 months with mild wheezing, and this limit can be used to avoid unplanned hospital admissions. There is an association between early respiratory syncytial -virus infections and subsequent wheezing and asthma, in that such infections select children who are prone to wheezing and asthma before school age, but the symptoms tend to decrease with time and an early respiratory syncytial -virus infection will not permanently alter bronchial reactivity<br>Tiivistelmä Hengitysvaikeus on yleinen oire lapsilla virusten aiheuttamien hengitystieinfektioiden yhteydessä. Kurkunpäätulehdukseen liittyy sisäänhengitysvaikeus. Ilmatiehyttulehdukseen, ahtauttavaan keuhkoputkentulehdukseen ja akuuttiin astmakohtaukseen liittyy uloshengitysvaikeus. Hengitystieinfektioihin liittyvä hengitysvaikeus on yksi yleisimmistä syistä päivystyspoliklinikkakäynteihin ja äkillisiin sairaalahoitojaksoihin lapsipotilailla. Hengitystieinfektioiden taudinkulun tuntemisella ja hengitysvaikeuden vaikeusasteen arvioinnilla on tärkeä merkitys näiden potilaiden hoidon toteuttamisessa. Hengitystieinfektioon liittyvää hengitysvaikeutta on pidetty riskitekijänä astman kehittymiselle. Tämän tutkimuksen tarkoituksena oli selvittää kurkunpäätulehduksen riskitekijöitä ja sairaalahoitoon vaikuttavia tekijöitä hengitystieinfektioon liittyvän uloshengitysvaikeuden hoidossa sekä varhaislapsuudessa sairastetun hengitystieinfektion yhteyttä myöhempään astma- ja allergiasairastavuuteen. Tutkimukseen sisältyi kaksi rekisteriaineistoa ja yksi seurantatutkimusaineisto. Tutkimuksessa todettiin, että kurkunpäätulehduksen uusiutuminen on erittäin tavallista ja sisarusten ja vanhempien sairastama kurkunpäätulehdus on merkittävin riskitekijä kurkunpäätulehdukselle ja sen uusiutumiselle. Alle 6 kuukauden ikäisillä lapsilla ilmatiehyttulehduksen taudinkuva on epävakaa ensimmäisen 5 oirepäivän aikana. Kuume, matala happisaturaatioarvo ja respiratory syncytial -virusinfektio ennustavat osastohoidon ja invasiivisten toimenpiteiden tarvetta ilmatiehyttulehduksen yhteydessä. Yli 6 kuukauden ikäisillä lapsilla happisaturaatioarvo > 93 % ennustaa lievää taudinkuvaa hengitystieinfektioon liittyvän uloshengitysvaikeuden hoidossa. Käyttämällä tätä happisaturaatioarvoa raja-arvona, kun arvioidaan sairaalahoidon tarvetta, voidaan merkittävästi ja turvallisesti vähentää sairaalahoidon tarvetta lasten hengitystieinfektioon liittyvän uloshengitysvaikeuden hoidossa. Alle 6 kuukauden iässä sairastettu respiratory syncytial -virusinfektio on riskitekijä varhaislapsuudessa ilmeneville astmaoireille, mutta tämä riski vähenee iän myötä ja 8 vuoden iässä ei ole havaittavissa eroja astma- ja allergiasairastavuudessa, kun verrataan näitä potilaita muun hengitystieinfektion sairastaneisiin potilaisiin ja terveisiin kontrollipotilaisiin
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Howat, Tom James. "Spatial dynamics of in vitro viral infection." Thesis, University of Cambridge, 2007. https://www.repository.cam.ac.uk/handle/1810/252041.
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Despite the importance of the IFNs in viral infections, many questions about the dynamics of IFN production and activity remain unanswered. Addressing these questions forms the first half of this thesis. It begins with an introduction to innate immunity, and a review of existing research. Focus then falls upon a simple experimental system: the <i>in vitro</i> infection of cell monolayers by Herpes simplex virus and the resulting IFN response. A stochastic spatial model of viral infection and consequent IFN production and activity is constructed. Using this model, simulations of infections under varying initial conditions suggest the existence of critical doses, at which the qualitative behaviour of infection changes. Implications for IFN activity <i>in vivo</i> infections are highlighted, as well as potential applications of the model, particularly in within-host modelling. The data used to parameterize this model come from widely used experiments called plaque assays: infection spreads in cell monolayers <i>in vitro</i>, leaving regions of dead cells, known as plaques. The second half of the thesis considers the dynamics of plaque formation and, in particular, the phenomenon of cometing, where in plaques unexpectedly streak across monolayers forming patterns that resemble comets. Several theories behind comet formation have been proposed in the literature, though the underlying mechanism is not understood. A detailed investigation is carried out here: previously voiced hypotheses are tested, and a method for controlling comet formation is developed; cometing is found to be a purely fluid dynamic phenomenon. The thesis concludes with an overview of the results obtained, and a discussion of potential applications and future directions for research.
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Christie, John Michael Landale. "Viral persistence in hepatitis C virus infection." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268465.
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Zhang, Lei Centre for Vascular Research Faculty of Medicine UNSW. "Understanding viral-immune dynamics in HIV infection." Awarded by:University of New South Wales. Centre for Vascular Research, 2005. http://handle.unsw.edu.au/1959.4/23372.
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The HIV epidemic has caused a health crisis globally. Using mathematical and statistical tools, we have analysed and modelled data from animal models of HIV, HSV and influenza virus, in order to understand the role of neutralising antibodies (nAbs), CD4+ T cells, CTLs and APCs in HIV infection and the implications of this for HIV vaccine design. Our analysis suggests that antibody and CTL responses confer protection at different stages of HIV infection. Passive antibodies confer protection against SHIV89.6PD infection by either neutralising the initial viral inoculum or reducing the acute viral level and growth. Consequently, CD4+ T cell preservation allows the immune system to control long-term disease progression. Therefore, vaccines that elicit high nAb levels during early infection may induce sterilising immunity or delay disease progression. By contrast, we observed that vaccine-elicited CTLs did not proliferate until day 10 following SHIV89.6P infection. More potent CTL-inducing vaccines did not reduce this delay, but further increased it and reduced CTL growth. However, more potent vaccines result in better memory CTL formation, better CD4 preservation and improved disease outcome. HIV vaccine design should aim to reduce the delay in CTL activation. To further understand the pathogenesis of HIV, we investigated the relationship between viral load and CD4+ T cell levels using simple ODE models. Our results demonstrate a positive correlation between peak viral level and the acute CD4+ T cell depletion in SHIV89.6P infection, which demonstrates how reduction of peak viral level significantly preserves CD4+ T cells. Surprisingly, this relationship between virus and CD4+ T cells was reversed in SIVmac239 infection and other CCR5 tropic infections. Future work should focus on understanding this difference between X4 and R5 infections. Regardless of viral infections, antigen presentation is essential for stimulating effective immune responses. Our study on influenza and HSV-1 infections suggests that antigen loading rate of APCs determines the magnitude of antigen presentation and the APC decay is mainly due to the degradation of pMHC, not CTL killing. The slow kinetics of HIV viral growth may be one factor that limits the level of antigen presentation and subsequent CTL response.
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Li, Wei Beck Melinda A. "Nutritionally-induced oxidative stress and viral infection." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,523.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.<br>Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition." Discipline: Nutrition; Department/School: Public Health.
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Lobbermann, Jens. "Regulation of immunity during viral lung infection." Thesis, Imperial College London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544288.
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Stevens, Kim. "Multiplicity of viral infection in brown algae." Thesis, University of Plymouth, 2014. http://hdl.handle.net/10026.1/3156.
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Brown algae are important primary producers and habitat formers in coastal environments and are believed to have evolved multicellularity independently of the other eukaryotes. The phaeoviruses that infect them form a stable lysogenic relationship with their host via genome integration, but have only been extensively studied in two genera: Ectocarpus and Feldmannia. In this study I aim to improve our understanding of the genetic diversity, host range and distribution of phaeoviruses. Sequencing and phylogenetic analysis of amplified fragments of three core phaeoviral genes (encoding major capsid protein (MCP), DNA polymerase and superfamily III helicase) of phaeovirus infected algae confirmed the suspected phaeoviral identity of viruses infecting E. fasciculatus, F. simplex, Pilayella littoralis, Myriotrichia clavaeformis and Hincksia hincksiae. Furthermore, this approach revealed multiple virus sequence variants within individual strains, and moreover that the variants formed two distinct subgroups. Subgroup A was highly conserved and observed in multiple algal genera, whereas subgroup B was much more diverse, but only found in Feldmannia species. Transcriptome sequencing of an actively infected F. irregularis strain revealed polymorphisms within key viral genes, suggesting that multiple variants were indeed active within this strain. High resolution melt curve (HRM) technology was used to develop a high throughput screening method for detecting phaeoviral MCP as a proxy for detection of phaeoviruses. This technique was also able to assign 88% of those detected to one of the subgroups, based on their differing melting temperature distributions. This was then applied to 1034 Ectocarpus isolates collected from around Europe and South America, and in accordance with previous studies of phaeoviral infection, 43-79% of strains contain virus sequence (depending on species). 17% of the isolates tested even contained sequence from both subgroups. 82 Laminariales strains, close relatives of the Ectocarpales, were also screened because they comprise commercially important kelp species but are not known to be infected by viruses. 10-17% of these tested positive for phaeoviral MCP, which when sequenced formed a separate group within the phaeoviruses. This finding could have a major impact on the kelp farming industry if the viruses are found to affect reproduction as happens in the Ectocarpales. The discovery of two subgroups is contrary to current beliefs that the phaeoviruses are a single monophyletic group, and that each species of alga has its own phaeovirus, casting doubt on the usefulness of the current convention of naming each phaeovirus after its host. It appears that the subgroup B viruses have begun to evolve away from the stable, K-selected subgroup A viruses towards a more r- type strategy with higher mutation and diversification. This study has identified potential mechanisms that may influence this shift, including mutations in a region of the DNA polymerase known to negatively affect DNA replication fidelity, combined with an active integrase and lack of a proofreading exonuclease, along with the observed infection of individuals with both phaeovirusal subgroups. The resulting mutations and recombinations could lead to the diversity observed here, and may provide a suitable model for the study of other emergent virus infections.
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Barasheed, Osamah Abdullah A. "Prevention of respiratory viral infection among Hajj pilgrims." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/23506.
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Hajj is one of the five basic tenets of Islam. Every practicing, financially and physically capable, Muslim is required to perform Hajj at least once in his/her lifetime. Each year up to three million people from more than 180 countries assemble in Mecca, Saudi Arabia, to perform Hajj pilgrimage. Severe crowding, shared accommodation, poor personal hygiene, and environmental pollution at Hajj may collectively lead to increased transmission of respiratory viruses. Influenza-like illness (ILI) is one of the most common medical presentations to primary care, mostly due to viral infection, in which pneumonia is the leading cause of hospital admission during Hajj. Therefore, I endeavoured to study the epidemiology of respiratory viruses among pilgrims including newly emergent viruses such as Middle East coronavirus (MERS-CoV) and assessed preventive strategies primarily focussing on facemasks effectiveness and evaluating influenza vaccine uptake. Methods To understand the epidemiology of respiratory infection during Hajj, a cross-sectional study was conducted among pilgrims from Saudi Arabia, Australia and Qatar. A nasal swab was collected from any participant who developed ILI to identify the causative agent. After that, we explored the possible preventive measures to reduce the transmission of respiratory viral infection such as influenza vaccine and facemasks. For influenza vaccine, an anonymous survey was conducted to assess the uptake of influenza vaccine, and explore the attitudes and barriers to, and perception of vaccination. At the same time, a pilot trial was conducted to explore the feasibility of establishing a large-scale trial to test the effectiveness of facemasks in preventing respiratory viral infection among Hajj pilgrims. The outcome of the pilot trial was encouraging and suggested that it was feasible to do a large-scale trial. Therefore, we conducted a large-scale randomised controlled trial (RCT) to test the effectiveness of facemasks in preventing respiratory viral infection over three consecutive Hajj seasons (2013, 2014, 2015). Results In 2013, we recruited 1038 pilgrims from Saudi Arabia, Australia and Qatar during the first day of Hajj and followed them closely for four days to comprehend the epidemiology of respiratory viral infection during the Hajj. About 11% of the pilgrims reported ILI; 38% of which had laboratory-confirmed viral infections. Rhinovirus was the commonest cause of ILI among Hajj pilgrims (25%) followed by influenza A (4%). Also, other types of viruses were reported such as adenovirus (2%), human coronavirus OC43/229E (2%) and parainfluenza virus 3, 1 (2%). MERS-CoV was considered a health risk at that year (2013), luckily, it was not detected in any sample in this study. The studies showed that influenza vaccine uptake was increased among Hajj pilgrims specifically the Australian. On the other hand, symptoms of respiratory infection were decreased. However, it is uncertain if this decrease is due to vaccination. Contrarily, facemasks uptake among Hajj pilgrims remained unchanged in the last 10 years with an average uptake of 50% according to a systematic review synthesised by myself and colleagues. Moreover, the large-scale RCT showed that pilgrims did not use facemasks adequately; and those who used facemasks had no statistically significant benefit against laboratory-confirmed or clinical viral respiratory tract infections. Conclusion Epidemiology of virus infection during Hajj showed that rhinovirus was the most common causative agent. Also, there were other respiratory viruses reported including influenza, adenovirus but not MERS-CoV. Influenza vaccine uptake is improving among Hajj pilgrims, while facemasks had lower uptake. Facemasks use did not prevent clinical or laboratory-confirmed respiratory viral infection during Hajj. This is may be due to poor compliance of pilgrims in using facemasks.
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Manley, Grace C. A. "The roles of DUSPs in respiratory viral infection." Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/19257/.
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Karrer, Urs. "Mouse cytomegalovirus infection as a model for persistent viral infections in mice and humans." Thesis, Open University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422034.
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Caney, Sarah Madeline Amanda. "Mucosal immunopathogenesis of feline immunodeficiency virus infection." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341499.
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Hussain, Imran Raza. "The immunobiology of respiratory syncytial virus infection." Thesis, University of Southampton, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289569.
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Eleftheriou, Androulla Anastasiou. "Viral infection among Thalassaemia major patients with special reference to Hepatitis C virus infection." Thesis, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265118.
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Dhenni, Rama B. S. "Role of Granzyme B in the Susceptibility to Secondary Bacterial Infection after Viral Infection." University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460446984.
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Leong, Iona Tuling. "Oral non-Hodgkin's lymphomas and Epstein-Barr viral infection." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0028/MQ34046.pdf.
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Dovigi, Allan Webster-Cyriaque Jennifer. "HIV salivary gland disease a role for viral infection /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2005. http://dc.lib.unc.edu/u?/etd,297.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2006.<br>Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Master of Science in the Department of Oral and Maxillofacial Pathology School of Dentistry." Discipline: Oral and Maxillofacial Pathology; Department/School: Dentistry.
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Karlsson, Annika C. "Viral dynamics and evolution following primary HIV-1 infection /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4558-6/.
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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.<br>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.<br>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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Gramoustianou, Evangelia Sophia. "Viral and host gene expression during human cytomegalovirus infection." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444419/.
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HCMV infection is usually asymptomatic in immunocompetent hosts, but serious disease can occur in immunocompromised individuals and in congenitally infected newborns. The importance of virus fitness determinations became evident in 1976, when it was proposed that the infecting strain of HCMV is important for clinical outcome, along with the intensity and duration of viral replication. HCMV strains exhibit different levels of virulence in vivo, depending on their passage history in cell culture. High and low passage HCMV strains exhibit tropism differences in vitro, suggesting that different tissue tropism may occur in vivo. In addition, approximately 13kb of novel DNA sequences located near the right edge of the unique long component of the genome has been identified in Toledo and clinical strains. This region (UL/b') encodes several open reading frames, which are missing from the high passage laboratory-adapted variants of Towne and AD 169 and are thought to play important roles in pathogenesis. One of the aims of this thesis was to determine the replication dynamics of different HCMV strains in vitro as well as compare their ability to bind to cells and mediate cell-to-cell spread of infection using pair-wise competition experiments in cell culture. AD 169 was shown to replicate better than Toledo in fibroblasts. Furthermore, assessment of the replication of Toledo in a different cell type, HUVEC, indicated that the virus replicated to higher levels in fibroblasts. Towne was found to bind to HEL cells with higher affinity compared to AD 169. The results showed phenotypic differences between high and low passaged HCMV variants and also illustrated that fitness differences between them are variable and highly dependent upon the status of the virus inoculum. To begin to understand the complex relationship between tissue tropism, virulence and HCMV genome composition, a DNA microarray approach was developed to examine host and HCMV gene expression during the productive infection of two distinct cell lines, fibroblasts and endothelial cells. The results showed that genes wifrojn tye fPSIPp were expressed in a cell type-specific fashion. Ip the context of host cell gene expression, cell type-specific host gene transcriptional changes were observed, reflecting different viral modulation of distinct cell type environments. The results provided potential insight into the function of genes encoded in the UL/b' region. Of particular note was that transcriptional changes frequently occurred in genes associated with pathways involved in the pathology of HCMV in the human host.
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Jorfi, Samireh. "The role of microvesicles in cancer and viral infection." Thesis, London Metropolitan University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590129.
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Microvesicles are shed constitutively, or upon activation from both normal and malignant cells. Although recent studies have reported various nonlytic virus release mechanisms, this mode of virus transmission to secondary sites of infection has remained unclear. This study identified that Coxsackie virus B1 (CVB1) entry into HeLa cells results in apoptosis and production of virus-induced apoptotic microvesicles (vaMVs) by infected cells. Flow cytometery and fluorescence microscopy data illustrated that these vaMVs carry and disseminate CVB1 virions to new host cells via a non lytic MV-to-cell viral mechanism. Inhibition of MV production by siRNA knockdown of CAPNS1 in HeLa cells suggested that these vesicles mediate the spread of apoptosis to secondary sites of infection and the vaMVs could mediate non lytic MV-to-cell transmission. This thesis also identified a new mechanism for multi-drug resistance involving the efflux of anticancer drugs from cancer cells mediated by release of microvesicles, removing the drug from treated cancer cells. Immunoblotting and flow cytometery data showed that transcriptional silencing of calpain by siRNA knockdown of CAPNS1 in PC3M cells prior to drug treatment inhibits MV release and results in induced apoptosis in cells. This mechanism contributes to understanding the reasons for insensitivity to drug-induced apoptosis and the induction of drug-detoxification by cancer cells. This study has yielded important information about how to circumvent drug resistance to improve cancer chemotherapy. Furthermore, fluorescence microscopy results postulate that induction of MV release with agonist agents and anticancer drugs, results in damage to the host plasma membrane, which must be resealed immediately using activated Iysosomes if the host cell is to survive and proliferate.
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Dillon, Amanda Louise. "Protozoan grazing and viral infection of freshwater synechococcus species." Thesis, Lancaster University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.536035.
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Jones, Joshua David. "Found in translation : tracking the ribosome during viral infection." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709233.
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Lissauer, Samantha Mary. "Modelling hepatitis C viral host interaction and co-infection." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8774/.
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Hepatitis C Virus (HCV) is a clinically important infection that leads to chronic liver disease and Human Immunodeficiency Virus (HIV) co-infected patients have more rapid progression to severe liver disease and show higher rates of HCV vertical transmission. Hepatocytes are a highly differentiated cell type and support low level HCV replication. Most studies of the viral life cycle use de-differentiated hepatoma cell lines, which are highly permissive. The mechanism behind this difference is poorly understood. We show that dimethylsulfoxide (DMSO) differentiated Huh-7 cells have a 100-fold reduction in permissivity to HCV infection. We confirm that these cells are differentiated and upregulate key liver specific markers including miR122. They are metabolically active and have intact innate signaling pathways in response to infection. We observed a 10-fold reduction in the initiation of replication and a 10-fold loss in extra-cellular particle infectivity. In contrast cell-to-cell dissemination rates were comparable and cell-contact dependent infection of differentiated cells can overcome the restrictions seen in cell-free infection. HCV cell-to-cell transmission can also be mediated by other cell types. T cells are the primary cell supporting HIV-1 infection. We have shown that HCV can bind primary and immortalized T cells and trans-infect hepatoma cells. This requires replicating HIV but is independent of co-receptor engagement. HIV-1 infection of CD4+ T cells induces a significant increase in HCV trans-infection by increased viral binding. T cells provide a vehicle for HIV-1 to promote HCV infectivity, transmission and persistence.
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Kauffman, Anne Kathryn Marie. "Demographics of lytic viral infection of coastal ocean vibrio." Thesis, Massachusetts Institute of Technology, 2014. http://hdl.handle.net/1721.1/90046.
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Thesis: Ph. D., Joint Program in Biological Oceanography (Massachusetts Institute of Technology, Department of Civil and Environmental Engineering; and the Woods Hole Oceanographic Institution), 2014.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references.<br>Viral predation on bacteria in the ocean liberates carbon from the particulate fraction, where it is accessible to higher trophic levels, and redirects it to the dissolved fraction, where it supports microbial growth. Although viruses are highly abundant in the ocean little is known about how their interactions with bacteria are structured. This challenge arises because the diversity of both bacteria and viruses is exceedingly high and interactions between them are mediated by specific molecular interactions. This thesis uses heterotrophic bacteria of the genus Vibrio as a model to quantify virus-host interactions in light of host population structure and ecology. The methods developed in this thesis include streamlining of standard bacteriophage protocols, such as the agar overlay, and facilitate higher throughput in the isolation and characterization of novel environmental virus-host systems. Here, >1300 newly isolated Vibrio are assayed for infection by viral predators and susceptibility is found to be common, though total concentrations of predators are highly skewed, with most present at low abundance. The largest phylogenetically-resolved host range cross test available to date is conducted, using 260 viruses and 277 bacterial strains, and highly-specific viruses are found to be prevalent, with nearly half infecting only a single host in the panel. Observations of blocks of multiple viruses with nearly identical infection profiles infecting sets of highly-similar hosts suggest that increases in abundance of particular lineages of bacteria may be important in supporting the replication of highly specific viruses. The identification of highly similar virus genomes deriving from different sampling time points also suggests that interactions for some groups of viruses and hosts may be stable and persisting. Genome sequencing reveals that members of the largest broad host-range viral group recovered in the collection have sequence homology to non-tailed viruses, which have been shown to be dominant in the surface oceans but are underrepresented in culture collections. By integrating host population structure with sequencing of over 250 viral genomes it is found that viral groups are genomically cohesive and that closely-related and co-occurring populations of bacteria are subject to distinct regimes of viral predation.<br>by Anne Kathryn Marie Kauffman.<br>Ph. D.
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Al-Juboori, M. R. "Viral and parasitic diseases in patients with HIV infection." Thesis, Сумський державний університет, 2013. http://essuir.sumdu.edu.ua/handle/123456789/32230.
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The aim of our research was to analyze the dependence of clinical manifestations of infections with viral and parasitic etiology on the background of HIV infection from the level of CD4-lymphocytes.
When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/32230
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Lin, Adora A. "The CD4+ T cell response to CNS viral infection." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1235330516.
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Moissiard, Guillaume. "Induction, suppression, amplification of RNA silencing during viral infection." Université Louis Pasteur (Strasbourg) (1971-2008), 2007. http://www.theses.fr/2007STR13023.
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L’ARN silencing est un mécanisme de régulation négative de l’expression des gènes par des interactions entre molécules d’ARN. Un ARN double-brin est découpé par Dicer en “short-interfering (si)RNA” de 21 à 24-nt incorporant un “RNA-Induced Silencing Complex”, pour guider le clivage d’ARNm cible de manière séquence spécifique. Le silencing joue un rôle important dans la lutte antivirale chez les plantes. De plus, la plupart des phytovirus produisent des protéines suppresseurs de silencing. Le silencing peut être amplifié par l’activité d’ARN-dépendante ARN polymérases (RDR) cellulaires. Nous avons étudié l’ARN silencing au cours de l’infection par le Cauliflower mosaic virus (CaMV) et montré que les quatre protéines Dicer-like (DCLs) d’Arabidopsis étaient impliquées dans ce mécanisme. Nous avons analysé les interactions entre cinq suppresseurs et l’activité de RDR6 et identifié les DCLs associés à RDR6. Nous avons découvert que dans certains cas, RDR6 utilise le siRNA comme une amorce<br>RNA silencing is a mechanism involved in the suppression of gene expression through nucleotide sequence-specific interactions mediated by RNA. A double-stranded RNA is processed by Dicer into 21- to 24-nt RNAs, called short-interfering (si)RNA that incorporate into a RNA-Induced Silencing Complex, to guide cleavage target mRNA in a sequence-specific manner. RNA silencing plays important antiviral role in plants. In parallel, most of phytoviruses produce suppressor proteins to counteract RNA silencing. RNA silencing can be amplified through the activity of the cellular RNA-dependent RNA polymerase (RDR). We studied RNA silencing during Cauliflower mosaic virus (CaMV) infection. We found that the four Arabidopsis Dicer-like (DCLs) proteins are involved to produce two classes of viral siRNAs. Then, we analysed the interactions between five silencing suppressors and RDR6 and identified the DCLs associated to RDR6. We also showed that, at least in some cases, RDR6 uses small RNAs as primers
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Marques, Mariana Campos. "Cellular responses to viral infection : proteostasis and innate immunity." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22054.
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Mestrado em Biomedicina Molecular<br>Viruses are small opportunistic infectious agents. Virus entry, replication and assembly are dynamic and coordinated processes that require precise interactions with host components, often with cellular organelles. Hence, we proposed to study two different viruses affecting two distinct cellular surveillance mechanisms: Human Cytomegalovirus (HCMV) and Influenza A Virus (IAV) influence on the innate immune response and proteostasis, respectively.
HCMV might be associated with additional long-term health consequences in human due to its ability to establish a lifelong persistent latent infection. HCMV encodes vMIA, an anti-apoptotic protein known to co-localize at peroxisomes and mitochondria, induce their fragmentation and inhibit the downstream cellular antiviral response that is established at both organelles. In the present work, we aimed to characterize the role of vMIA in the peroxisomal-MAVS dependent antiviral response. We proposed to map the vMIA domains responsible for the organelles’ morphology changes and innate immune response inhibition. Our results revealed that the 115-130 amino acid sequence might be important for the organelles’ fragmentation. We also found that m38.5, an analogue of vMIA in murine CMV (MCMV) seems to localize at peroxisomes, induce the organelle’s fragmentation and clearly inhibit the peroxisome-dependent antiviral immune response. These results suggest that this virus may be useful to complement our results with experiments performed in animals or in the context of a viral infection.
IAV is the causative agent for most of the annual epidemic in humans. During IAV infection, it occurs the accumulation of unfolded proteins and the formation of specialized sites of viral replication, resulting in the formation of insoluble aggregates or inclusions. In this study, we proposed to determine whether and how IAV infection leads to aggresomal-prone proteins accumulation. Our preliminary results suggest aggresomes formation during viral infection, previous to the vRNP release in to the cytoplasm.<br>Os vírus são agentes infeciosos oportunistas. Os diferentes passos de um ciclo de vida viral, incluindo a entrada do vírus na célula, a replicação do seu genoma e a formação de novas partículas virais requerem interações com os diferentes componentes celulares do hospedeiro, nomeadamente com organelos. Neste projeto, propomos estudar dois tipos diferentes de vírus que afetam dois mecanismos distintos de sobrevivência celular: a influência do Citomegalovírus de humano (HCMV) na resposta imunitária inata e o efeito do Vírus da Influenza A (IAV) na proteostase.
O HCMV pode estar associado com consequências graves para a saúde da população, uma vez que tem a capacidade para estabelecer uma infeção latente e persistente no hospedeiro. Este vírus codifica para a vMIA, uma proteína anti-apoptótica que se localiza nos peroxissomas e nas mitocôndrias, induzindo a sua fragmentação e inibindo a resposta antiviral celular que é estabelecida em ambos. Com isto, sugerimos mapear os domínios da vMIA responsáveis pelas alterações na morfologia dos organelos e na inibição da resposta imune. Os nossos resultados revelaram que a sequência de aminoácidos 115-130 poderá ser importante para a fragmentação dos organelos. Também descobrimos que a proteína m38.5 do Citomegalovírus de ratinho (MCMV), análoga à vMIA, parece localizar nos peroxissomas, induzir a sua fragmentação e claramente inibir a resposta antiviral dependente deste organelo. Estes resultados sugerem que este vírus poderá ser útil para complementar os nossos resultados com experiências animais ou no contexto de infeção viral.
O IAV é o agente causativo da maioria das epidemias anuais em humanos. Durante a infeção com IAV, ocorre acumulação de proteínas com conformação errada e a formação de locais especializados de replicação viral, resultando na formação de agregados insolúveis ou inclusões. Neste estudo, propusemos determinar se a infeção com IAV conduz à acumulação de proteína com pré-disponibilidade para formar agressomas. Os nossos resultados, embora preliminares, sugerem que existe formação destas estruturas durante a infeção viral, previamente à libertação do genoma viral no citoplasma.
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Hauler, Felix. "The ATPase VCP in viral infection and antiviral immunity." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707973.
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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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Cootes, Taylor Ann. "Dietary regulation of the host response to viral infection." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/28614.
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Host factors, such as genetics and aging, are known to regulate the severity of influenza. However, the role of environmental factors in the viral infection remains poorly defined. By altering individual nutrition components or energy density, animal studies have clearly demonstrated that diet modulates the outcome to influenza in mice. However, it remains unclear whether energy-balanced diets, known to be sufficient in supporting the health of naïve animals, are adequate in mediating the survival of the infected host. This thesis work was set to investigate whether diet quality, independent of energy and macronutrient intake, controls the outcome of influenza virus infection in mice and the mechanisms that underlie it.
In Chapter 3, I determined whether mice fed on two commonly used laboratory diets, chow and AIN93G, are equally efficient in supporting host defence against IAV infection. I observed that mice fed on AIN93G exhibited increased mortality following the infection. Interestingly, the increased susceptibility was not due to impaired induction of antiviral immunity or pathogen control but instead due to perturbed physiological function and failure to restore homeostasis following infection. These findings reveal that isocaloric diets with differing qualitative composition regulates host fitness, rather than pathogen clearance.
To understand the mechanisms underlying the altered physiological function in AIN93G-fed mice, I elucidated the transcriptional responses in organs important for regulating vital physiological functions, such as body temperature and appetite, in chapter 4. While displaying comparable gene signatures before infection, chow and AIN93G-fed mice exhibited distinct transcriptomic profiles following infection, particularly in the hypothalamus and BAT. While the expression of genes relating to the immune response were comparable between in chow and AIN93G-fed mice, the expression of the genes involving cell differentiation was altered significantly in latter animals, uncovering a potential transcriptional mechanism for the dysregulated thermoregulation observed in AIN93G-fed mice.
In chapter 5, I demonstrated that mice maintained on purified diets with varying protein and carbohydrate ratios showed differential susceptibility to infection, thereby demonstrating definitively that the dietary variations in energy- balanced diets are sufficient in altering the outcome of influenza virus infection. Cytokines have been established as being responsible for the perturbed physiological functioning that occurs during infection. In the second part of this chapter, I investigate the role of IFN-gamma in regulating host fitness in mice fed purified diets and demonstrated that IFN-gamma receptor deficient mice fed on AIN93G are completely protected from influenza virus infection, revealing a diet-dependent detrimental function for IFN-gamma to influenza.
These findings reveal diet as a crucial environmental factor that determines host fitness and uncover mechanisms underlying the preservation of physiological homeostasis necessary for survival to influenza virus infection.
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Donahue, Daniel. "The role of viral reservoirs in HIV-1 infection." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119565.
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The major source of virus production during human immunodeficiency virus type 1 (HIV-1) infection is activated CD4 T-cells, although infection of some other cell types can also contribute to virus production. A viral reservoir is either a cell type or an anatomical site whose properties can result in the persistence of infectious virus for a longer time period than the primary source of virus production, and several different HIV-1 reservoirs are known to exist. The work presented in this thesis examines three different aspects of viral reservoirs in HIV-1 infection. The first part (Chapter 2) is an investigation of the role of long-lived virus-producing cells during antiretroviral therapy. Specifically, cell culture experiments were designed that have resulted in a further understanding of the inhibition of HIV-1 replication in viral reservoirs. The second and third parts of this thesis (Chapters 3 and 4) consider the role of latently infected CD4 T-cells in HIV-1 infection. Latently infected cells carry an HIV-1 genome that is integrated into the cellular chromatin and does not produce viruses, but that retains the capacity for infectious virus production in the future. These cells form the latent reservoir, which represents the major barrier to an HIV-1 cure and necessitates life-long antiretroviral therapy for infected individuals. The work presented in Chapter 3 demonstrates that it is possible to inhibit the establishment of latent infection in vitro, something that has not yet been achieved clinically. Chapter 4 considers the potential contribution of latent viruses to viral genetic diversity, and shows that latent viruses can contribute to the development of multidrug resistance. In summary, the work presented in this thesis provides for a greater understanding of the role of viral reservoirs in HIV-1 infection and of the ability of antiretroviral drugs to combat infection.<br>Les cellules T CD4 activées sont la principale source de virus pendant l'infection par le virus de l'immunodéficience humaine (VIH-1) même si d'autres cellules contribuent à la production virale. Un réservoir viral est un type de cellule ou un compartiment anatomique dont les propriétés permettent la persistance du virus infectieux pour plus longtemps que la source majeure de la production virale et le VIH-1 occupe plusieurs réservoirs. Dans cette thèse, nous examinons trois différents aspects des réservoirs du VIH-1. Dans la première partie (Chapitre 2), nous avons étudié le rôle des cellules à grande longévité qui produisent du virus dans la thérapie anti-rétrovirale. En particulier, nous avons étudié en culture cellulaire comment inhiber la réplication virale dans ces cellules. Dans la deuxième et troisième partie (Chapitres 3 et 4), nous avons étudié le rôle de la latence dans les cellules T CD4. Les cellules latentes contiennent le génome du VIH-1 intégré dans leur chromatine sans produire du virus. Néanmoins, ces cellules peuvent produire du virus infectieux dans le futur et sont un obstacle majeur contre la guérison des individus vivants avec le VIH, ce qui les oblige à prendre des médicaments pour toute leur vie. Dans le Chapitre 3, nous montrons qu'il est en théorie possible d'empêcher l'infection latente, ce qui n'a jamais été fait en clinique. Finalement, le Chapitre 4 étudie le rôle du virus latent dans la diversité génétique du VIH, et montre que les virus latents peuvent participés à l'émergence de la résistance contre plusieurs médicaments. En résumé, le travail de cette thèse contribue à une meilleure compréhension du rôle des réservoirs viraux dans l'infection au VIH-1.
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Christiaansen, Allison Fae. "T cell regulation of acute and chronic viral infection." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/6076.
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A balanced immune response is required to mediate clearance of a virus infection without immune-mediated disease. CD4 and CD8 T cells are capable of both exerting antiviral effector functions and regulating the immune response. The regulatory T cell (Treg) subset of CD4 T cells helps to modulate immune activation and inflammation. During respiratory syncytial virus (RSV) infection in mice, conventional CD4 T-cell-mediated cytokine production has been shown to contribute to immune-mediated pathology. I demonstrate that Tregs are critical to control immunopathology during RSV infection. This was demonstrated through diphtheria toxin (DT)-mediated Treg elimination in a mouse strain expressing the DT receptor (DTR) under the control of the Foxp3 promoter. However, these mice were unable to maintain extended Treg depletion limiting the effectiveness of this model. In addition, DT-treated wild-type (WT) mice were found to be a necessary control for adverse DT-induced disease. In humans, I have shown that activated Tregs are reduced in the peripheral blood of RSV-infected infants compared to controls. RSV-infected infants also exhibited an increased proinflammatory cytokine response in nasal aspirates. However, the alarmin cytokine IL-33, which has been shown to mediate Treg homeostasis, was the only cytokine that exhibited reduced protein levels in RSV-infected infants compared to controls. Thus, severe RSV infection in infants may be due to lack of proper Treg-mediated immune regulation.
Similar to RSV, regulation of the T cell response during chronic viral infection with lymphocytic choriomeningitis virus (LCMV) is vital to prevent immune-mediated pathology. During LCMV and human chronic viral infections, CD4 and CD8 T cells exhibit T cell exhaustion where they lose the ability to exert effector functions. However, a functional CD4 and CD8 T cell response is required for viral clearance. During human chronic viral infection, an association between increased CD4 and CD8 T cell function and enhanced viral control has been identified that can be influenced by genetic factors. I aimed to identify the contribution of the host genetic factors that contribute to enhanced CD8 T cell function and viral control using the LCMV model. I found that increasing the major histocompatibility complex (MHC) diversity resulted in enhanced viral control in both a C57BL and BALB genetic background. Thus, induction of a broader T cell response was associated with enhanced viral control. However, mice expressing a heterozygous MHC on the C57BL background also exhibited mortality following chronic viral infection. Both CD4 and CD8 T cells were shown to contribute to this mortality and exhibited reduced T cell exhaustion during LCMV infection in these mice. Heterozygous MHC expression on the C57BL mouse background was also associated with an increased T helper (Th)-1 skewed CD4 T cell response compared to mice on the BALB background. Furthermore, CD4 T-cell-mediated IFN-γ production contributed to both CD8 T cell effector activity and mortality during chronic LCMV infection. Thus, both T cell epitope diversity and host genetics contribute to LCMV-induced mortality. Collectively, my data highlight both the need for effective immune-meditated viral control and regulation of T-cell-mediated pathology during both acute and chronic viral infections.
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CORTESE, MARIA FRANCESCA. "HIV and HBV infection as models of viral DNA integration and mechanisms of viral-associated carcinogenesis." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2015. http://hdl.handle.net/2108/203036.
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My PhD was focused on two viruses, both responsible of persistent infection: HIV and HBV. The
two viruses show high worldwide prevalence and both are associated with high morbidity and
mortality.
HIV establishes a persistent infection through different mechanisms, first of all with the integration
of its DNA into the host genome, thus forming the provirus. However, a consistent part of the viral
DNA within the infected cells is unintegrated (circular or not). The project following presented
aims to analyse the kinetic of viral replication (measured as p24 production) and HIV DNA integration in primary lymphocytes (CD4+ ad PBMC) and Monocyte-derived Macrophages (MdM)
in presence and absence of Integrase inhibitors (INIs). HIV DNA quantification (as proviral,
unintegrated and 2-LTR) was assessed at different time points. The presented data reconfirmed, as
previously reported in literature, the different kinetic of HIV replication in lymphocytes (CD4+ T
cells and PBMCs, much faster) compared to macrophages (more slow), and suggested the presence
of a different kinetic of HIV DNA integration between the two cellular systems, too. Both INIs
efficiently inhibit the viral replication and the integration of HIV DNA. However, a little but
consistent amount of HIV DNA was observed at 30 days post treatment in macrophages, which are
the main reservoirs of the infection. By analysing the composition of this little HIV DNA amount,
we observed a very little difference between the two drug which could be probably explained by the
well-described different kinetic of dissociation of the DTG-enzyme complex. In conclusion these
data could give new information about the different kinetic of HIV replication between
lymphocytes and macrophages, suggesting also the implication of a different kinetic of HIV DNA
integration. Both the integrase inhibitors efficiently inhibit HIV replication and integration.
Nonetheless, in presence of INI, although an almost total inhibition of HIV replication was
observed, a little but consistent amount of viral DNA was maintained in macrophages. This
evidence could have important implication in the study of HIV persistence and viral rebound after treatment interruption. The data above mentioned were presented at the 12th edition of the
European congress on HIV e hepatitis, in Barcelona in 2014 (26-28 March), and a manuscript is in
preparation.
HBV is another important virus able to establish a persistent infection that usually causes cirrhosis
and hepatocarcinoma (HCC). HBV could indirectly (through compensative cellular replication) or
directly (through event of random integration or due to the viral proteins) promote carcinogenesis.
Among the viral proteins the trans-activating HBV protein (HBx) covers a key role in this sense.
The project here presented aims to highlight specific mutations in HBX gene associated with HCC
in a group of chronically-HBV infected patients. By analysing the sequences of 75 HBV chronically
infected patients, we observed the mutation F30V prevalently in the HCC group. This is located
within the N-terminal region of HBx which seems to be involved in the negative regulation of the
HBx trans-activation function. By analysing the results obtained in vitro, we observed that the
mutation would reduce the viral replication, probably due to its localization in a domain within the
N-terminal region known to be involve in the dimerization of the protein. HBx protein, both wt and
mutated, did not alter the cycle progression of exposed cells. On the contrary, the mutation could to
be associated with less cellular susceptibility to apoptotic death related to what observed in
presence of the HBx wt. This observed cell survival could probably promote the maintenance of
aberrant cellular clones thus favouring the appearance of tumour. Of consequence, considering the
obtained results, it is possible to propose that F30V mutation could interfere with HBV replication
and can have a role in HBV-driven carcinogenesis by reducing the rate of apoptosis. However,
further studies are required in order to understand the potential role of F30V as HCC prognostic
factor in HBV chronically infected patients.
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Yao, Felix Caspar. "Investigation on the risk of viral infection in musculoskeletal grafts." University of Western Australia. School of Surgery, 2010. http://theses.library.uwa.edu.au/adt-WU2010.0068.
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[Truncated abstract] Around 50,000 hip and knee replacements are performed every year in Australia and this number has been increasing by around 13% annually since 1998 (Transplantation Society 2006). The incidence and number of revision surgery has increased by a similar proportion. Autogenous bone or allograft is still the gold standard grafting material and is currently used in a variety of reconstructive surgical procedures. The use of any allograft material carries with it the risk of transfer of disease from donor to recipient. These tissues can transmit the same viral and bacterial infections as blood, and the products of a single donation may be transplanted to several recipients. In contrast to blood, musculoskeletal tissues may come from surgical and cadaveric donation. Overall, the prevention of infection relies on the maintenance of rigid protocols for procurement, donor and allograft testing, secondary sterilisation, and the adherence to internal safety standards within the tissue banks. This thesis aims to determine the risk of viral infection among musculoskeletal tissue donors in Australia. We retrieved and analysed data retrospectively from three large tissue banks in Australia (Perth, Queensland, Victoria). This includes 12,415 musculoskeletal tissue donors, 10,937 of which are surgical donors and 1,478 of which are deceased donors, for the period of 1993 -2004. This data was analysed to determine the prevalence and incidence of viral infections such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human T-lymphotropic virus (HTLV) in musculoskeletal allografts. The results indicate that the risk of viral infection from musculoskeletal tissue transplantation in Australia is low. ... The results indicate that the overall prevalence of screened transfusion-transmitted viral infections did not vary significantly for musculoskeletal donors over the study period, despite falling in the general population and first-time blood donors. In tissue donors, HIV incidence significantly decreased over time, and HBV decreased significantly during 1999-2001; however, there was an apparent increase in the estimated incidence of HCV in 2002-2004 compared with earlier years. Furthermore the residual risk estimate of HIV in the period 2002-2004 has declined 5-fold compared to estimates in the period 1993-1995. This is perhaps due to greater awareness of high risk behaviours among donors, improvement in donor recruitment and an overall decrease in infection levels in the general population. Musculoskeletal tissue is second only to blood as the most frequent transplanted human tissue. Viral infection is a potential complication of tissue transplantation. In this thesis the rates of HIV, HBV, HCV and HTV infection in musculoskeletal donors in Australia were identified and then compared with results in published data from Canada, Scotland and the United States. The study also compared that result with first-time blood donors because they have satisfied similar donor selection criteria (Galea et al. 2006). The results indicate that prevalence and incidence estimates for viral infection in Australian tissue donors are higher than those in blood donors. This was also reported in studies from other countries. Accordingly, it is crucial that viral prevalence and incidence be monitored to evaluate the safety of tissue supply and to improve donor selection processes.
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Suhartha, Nina Aryani. "Regulation of α4β7 on naïve T cells upon viral infection". Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-164321.
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The elimination of virus-infected cells to block viral spread is substantially conveyed
by effector CD8+ T cells. Trafficking of naïve T cells into the lymph node is a crucial
step for their activation to effector T cells. The entry into the lymph nodes is mediated
by several cell adhesion molecules that are highly specific for given lymph nodes.
For the ingress into the gut-associated lymphoid tissue (GALT) such as mesenteric
lymph nodes and Peyer’s patches, the integrin α4β7 is the major homing receptor that
interacts with its main ligand MAdCAM-1. On naïve T cells, α4β7 is expressed at low
level, however upon activation in the GALT its expression is significantly upregulated
on effector T cells. Consequently these effector T cells migrate into the
gastrointestinal tract, where MAdCAM-1 is also expressed.
The migration patterns of virus-specific CD8+ T cells upon viral infection have been
studied in detail. In contrast, the migration of the major population of virus-unspecific
CD8+ T cells, i.e. bystander-activated T cells is poorly understood. In our study, we
aimed to determine how trafficking of these non-cognate, bystander-activated T cells
is affected upon viral infection.
We discovered that α4β7 expression was negatively regulated on bystander-activated
CD8+ T cells upon injection of poly (I:C), which imitates innate immune activation
upon viral infection. This effect was also observed for viral infections such as Sendai,
EMCV and the mutant form of VSV virus. Furthermore, we scrutinized the direct role
of IFN-α on T cells to exert α4β7 modulation. In the case of EMCV infection, IL-6
played a dominant role in the alteration of α4β7 expression. Finally, using an adoptive
transfer model we could prove that the downregulation severely impacted the
trafficking of T cells into the Peyer’s patches and to a lesser extent into the
mesenteric lymph nodes.
These findings demonstrate that a mechanism to regulate trafficking of
bystander-activated T cells during viral infection exists and that this is controlled by
the induction of cytokines such as IFN-α and IL-6. We hypothesize that the
downregulation of α4β7 on naïve T cells functions 1) to allow space for virus-specific
effector T cells to expand in the GALT and 2) to exclude bystander-activated T cells from the GALT in order to prevent mistrafficking, which could cause autoimmune
diseases.<br>T-Zellen spielen eine essentielle Rolle im Aufbau der adaptiven Immunität.
Die Migration von naiven T-Zellen in die Lymphknoten ist ein notwendiger Schritt für
ihre Aktivierung zu Effektor-T-Zellen. Der Eintritt in die Lymphknoten wird durch
verschiedene Zelladhäsionsmoleküle vermittelt, die hochspezifisch für bestimmte
Lymphknoten sind. Für den Zugang in das darmassoziierte lymphatische Gewebe
(GALT), wie mesenteriale Lymphknoten und Peyer-Plaques, ist das Integrin α4β7 der
Hauptrezeptor, der mit seinem Ligand MAdCAM-1 interagiert. Auf naiven T-Zellen ist
das Integrin α4β7 schwach exprimiert, jedoch wird es bei einer T-Zell-Aktivierung in
GALT hochreguliert. Folglich wandern die Effektor-T-Zellen in den gastrointestinalen
Trakt, in dem MAdCAM-1 ebenfalls exprimiert ist. Die Eliminierung von
virus-infizierten Zellen zur Hemmung der Ausbreitung von Viren wird wesentlich von
Effektor-CD8+-T-Zellen durchgeführt.
Während viele Studien über die Migration von virus-spezifischen CD8+ T-Zellen
bereits bekannt sind, wurde die Migration der überwiegend virus-unspezifischen
aktivierten CD8+ Population bisher nicht detailliert untersucht. In unserer Studie ist
das Ziel die Feststellung, ob die Migration dieser unspezifisch-aktivierten T-Zellen
während einer viralen Infektion verändert wird.
Durch unsere Experimente konnten wir zeigen, dass die α4β7 Expression auf
unspezifisch-aktivierten T-Zellen bei einer Stimulation mit poly (I:C), die virale
Infektion nachahmt, negativ reguliert wird. Diesen Effekt konnten wir auch in anderen
viralen Infektionen mit Sendai, EMCV und einem mutierten VSV-Stamm beobachten.
Des Weiteren konnten wir beweisen, dass IFN-α auf die T-Zellen eine direkte
Funktion zur Regulierung der α4β7 Expression ausübt. Im Falle einer EMCV Infektion,
spielt IL-6 eine beträchtliche Rolle in die Herabregulation der α4β7 Expression.
Letzendlich konnten wir durch ein Adoptiv-Transfer-Experiment bestätigen, dass die
α4β7 Runterregulation auf die Migration der unspezifisch-aktivierten T-Zellen in den
Peyer-Plaques und zum Teil in den mesenterialen Lymphknoten eine gravierende
Auswirkung hat.
Unsere Studie hat damit gezeigt, dass ein Mechanismus zur Regulierung der
Migration von unspezifisch-aktivierten T-Zellen während einer viralen Infektion existiert und diese durch induzierte Zytokine wie IFN-α und IL-6 beeinflusst wird.
Wir vermuten, dass die α4β7 Runterregulation auf naiven T-Zellen nachstehende
Funktionen hat. Erstens, erlaubt es den virus-spezifischen Effektor-T-Zellen in den
Lymphknoten zu expandieren. Zweitens, ist es möglicherweise eine
Präventionsmaßnahme, damit die unspezifisch-aktivierten T-Zellen nicht
versehentlich in den Darm geleitet werden, was zu einer Autoimmunerkrankung
führen könnte.
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Eddleston, Michael Philip. "Reactive astrocytosis after viral infection of the central nervous system." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336610.
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Ribeiro, Ruy Miguel. "Models of viral diversity and disease development in HIV infection." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302403.
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Graham, Christine Marian. "Anti-viral immunity : helper T cells in influenza virus infection." Thesis, Oxford Brookes University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444320.
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Katafigiotis, Sokratis. "Regulation of viral gene expression during infection with enteric viruses." Thesis, University of Nottingham, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.495601.
Full textAbstract:
In this study two enteric viruses, poliovirus and adenovirus type 40, were used to investigate virus - host cell interactions in the gastrointestinal environment. Human enteric adenoviruses have been previously shown to be sensitive to IFN-treatment of cells and a STAT-deficient cell line allows improved growth of enteric adenovirus type 40. Two adenoviral gene products, the virus-associated RNA (VA RNA) and the El A, have been previously shown to be responsible for viral countermeasures against IFN actions in the host cell.
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Lee, Debbie Ching Ping. "Regulation of immune responses and viral persistence in RSV infection." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503821.
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Razvi, Enal Shahid. "T Lymphocyte Apoptosis and Memory in Viral Infection: A Dissertation." eScholarship@UMMS, 1994. http://escholarship.umassmed.edu/gsbs_diss/263.
Full textAbstract:
Acute viral infections in humans and mice induce T lymphocyte responses which mediate viral clearance and result in the establishment of immunological memory. The course of an immune response to acute viral infection is associated with an immune deficiency in the lymphocyte compartment. This is usually characterized by the inability of lymphocytes to productively respond to mitogen or recall antigen. This thesis examined the acute lymphocytic choriomeningitis virus (LCMV) infection of the mouse and showed that T lymphocytes isolated from acutely LCMV-infected mice underwent activation-induced apoptosis upon signalling through the T-cell receptor (TcR)-CD3 complex. Kinetic studies demonstrated that this sensitivity to apoptosis directly correlated with the induction of immune deficiency, as measured by impaired proliferation in response to anti-CD3 antibody or to concanavalin A. Cell cycling in interleukin-2 (IL-2) alone stimulated proliferation of LCMV-induced T cells without inducing apoptosis, but preculturing of T cells from acutely-infected mice in IL-2 accelerated apoptosis upon subsequent TcR-CD3 crosslinking. T lymphocytes isolated from mice after the acute infection were less responsive to IL-2, but IL-2 receptor-bearing T cells, presumably memory T cells, responding to IL-2 were primed in each case to die a rapid apoptotic death upon TcR-CD3 crosslinking. These results indicated that virus infection-induced unresponsiveness to T-cell mitogens is in part attributable to apoptosis of the activated lymphocytes and suggest that the sensitization of memory cells by IL-2 and other stimulatory cytokines induced during an acute infection will cause them to die upon antigen recognition, thereby impairing specific responses to nonviral (recall) antigens.
The cytotoxic T lymphocyte (CTL) response to acute LCMV infection is characterized by a massive (10-20 fold) expansion of CD8+ cell number, which after clearance of virus declines in number and returns to levels present prior to infection. This thesis documents the presence of high levels of apoptotic lymphocytes in situ in the spleens of mice during the silencing of the immune response to acute LCMV infection. Apoptotic cells were detected by an in situ nucleotidyl transferase (ISNT) assay. Both T and B lymphocytes, as revealed by immunohistochemical analysis, are shown to be dying in vivo, the latter in clusters. A biphasic occurrence of apoptosis during the course of the acute infection was found, with an increase in numbers of apoptotic cells above background at day 3 post-infection, and at day 11 post-infection, a second more pronounced peak coincident with the decline of the CTL response to the infection and with the decrease in total spleen leukocyte number. Apoptosis in vivo was detected in lpr mice lacking Fas expression, a molecule involved in lymphocyte apoptosis. Fas expression thus may not be required for lymphocyte apoptosis in the context of an acute viral infection. Apoptosis in situ and the silencing of the CD8+ T lymphocyte response to acute LCMV infection were unaffected by the enforced lymphocyte-directed expression of Bcl-2, a protein blocking IL-2 deprivation-induced apoptosis of lymphocytes. Experiments aimed at addressing the role of Bcl-2-sensitive apoptotic pathways in the development of viral persistence revealed that high-dose infection of Bcl-2-transgenic mice results in death of the animals. Flow cytometric analysis showed an accumulation of Thy1.2+ T cells in the lungs of these animals, and the air spaces in the lungs were occluded with cellular and fluid infiltrates. These results suggest that the pathology seen in the Bcl-2-transgenic mice upon high-dose infection is perhaps immune response-mediated (an immunopathology). This is consistent with a role for Bcl-2-sensitive pathways of lymphocyte apoptosis in the pathogenesis of persistent LCMV infection.
The in situ demonstration of apoptosis in spleens during infection provide direct in vivo evidence for the death of lymphocytes during the recovery from an acute viral infection. This indicates that apoptotic elimination of the population en masse is a mechanism for halting an antiviral immune response upon clearance of virus. Furthermore, the data argue that IL-2 deprivation-driven apoptosis, upon clearance of virus, of the expanded T lymphocyte compartment is not the major mechanism involved in the silencing of the T cell response to acute LCMV infection.
Resolution of an acute immune response leads into the generation of longterm immunological memory. Since this thesis focussed on T cell responses in viral infection, it was important to characterize the in vivo state of memory CD8+ T cells. During acute LCMV infection, the majority of the LCMV-specific CTL activity tested immediately ex vivo was mediated by CD8+ L-selectin-Mac-1+ CTL. The L-selectin- population of CD8+ cells elicited during acute infection also carried >99% of the restimulatable CD8+ CTLp to LCMV, and these required added IL-2 for development into effectors in vitro. In contrast to the acute infection, most of the virus-specific CTLp in immune mice were L-selectin+.
Examination of CD8+ T cells in LCMV-immune mice revealed that a L-selectin+ blast-sized population of cycling CD8+ cells contained CTLp which developed into effector CTL in the absence of added IL-2. These cells also expressed Mac-1 and IL-2R. Flow cytometric sorting for IL-2R+ and IL-2R-CD8+ cells in the immune animal revealed, by limiting dilution analysis, similar frequencies of CTLp in both populations. In bulk restimulation assays, the CD25+ CTLp did not require added IL-2 for their in vitro development into effectors, whereas the CD25- CTLp did. Hence, the different requirements for CTLp to effector development in vitro reflect qualitative differences in the in vivo state of the CTLp in the various subpopulations.
LCMV-specific memory CTLp not requiring added IL-2 for differentiation were also found in the small-sized, non-cycling, CD8+L-selectin- cells. In contrast, the small-sized, non-cycling, CD8+L-selectin+, and CD8+IL-2R- populations also carried CTLp, but these required added IL-2 for development into effector CTL. Hence, T cell memory to LCMV is distributed among various lymphocyte subpopulations in immune animals, and the presence of an activated cycling cell component may account for the stability and long-term perpetuation of antiviral immunological memory.
In summary, the susceptibility of activated T lymphocytes to apoptosis probably explains an aspect of virus-induced immune deficiency and allows for the establishment of homeostasis subsequent to the resolution of an acute viral infection.
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McManus, T. E. "Viral infection and associated inflammation in chronic obstructive pulmonary disease." Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426766.
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Піддубна, Анна Іванівна, Анна Ивановна Поддубная, Anna Ivanivna Piddubna, Алекс Магуфва, Алекс Магуфва, and Alex Magufwa. "Clinical presentations of viral and parasitic diseases in HIV infection." Thesis, Одеський національний медичний університет, 2012. http://essuir.sumdu.edu.ua/handle/123456789/26618.
Full textAbstract:
Представлений аналіз залежності клінічних проявів інфекцій вірусної і паразитарної етіології на тлі ВІЛ-інфекції від рівня CD4-лімфоцитів.
При цитуванні документа, використовуйте посилання http://essuir.sumdu.edu.ua/handle/123456789/26618<br>Представлен анализ зависимости клинических проявлений инфекций вирусной и паразитарной этиологии на фоне ВИЧ-инфекции от уровня CD4-лимфоцитов.
При цитировании документа, используйте ссылку http://essuir.sumdu.edu.ua/handle/123456789/26618<br>Represented the analysis of dependence of clinical manifestations of infections with viral and parasitic etiology on the background of HIV infection from the level of CD4-lymphocytes.
When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/26618
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Wen, Li. "Immune responses to vaginal viral infection in a mouse model." Thesis, The University of Sydney, 1998. https://hdl.handle.net/2123/27666.
Full textAbstract:
Viral infection in the female reproductive tract is a global health problem, with high morbidity and mortality worldwide. However, immune protection of the female reproductive tract against virus infection is poorly understood. The aim of the study described in this thesis was to investigate the immune responses to vaginal West Nile virus (WNV) infection in an experimental mouse model, in an attempt to characterize the immune mechanisms involved in protecting the host against viral infection in the female genital tract. WNV is a neurotropic flavivirus which can infect both humans and animals, and which belongs to a virus family causing serious disease throughout the world. The mouse model of genital tract infection with WNV is not representative of the human situation; nevertheless, such models may be an appropriate tool to identify virus antigen components which may be effective in
eliciting protective immunity at the genital mucosal surface.
The progesterone-dominated mouse model is mainly used in the experiments of the present study. This model impairs the vaginal epithelial barrier, increasing the susceptibility of adult mice to vaginal virus infection. Virus-infected cells were detected in the vaginal epithelium of BALB/c mice from day 2 to day 7 after infection by immunoperoxidase labelling of WNV protein. A series of immune responses were evoked following vaginal WNV infection. Specific anti-WNV IgM and IgG antibodies were detected in vaginal washing by ELISA, associated with an increasing lgM and IgG containing cell infiltration, and a significant B220+ B cell infiltration in the vaginal mucosa. A correlated accumulation of B220+ B cells in the iliac lymph nodes (ILN) was detected by flow cytometry. B cells presented a major
cell population infiltrating in the vagina and proliferation in the ILN indicates that humoral immunity plays an important role against vaginal WNV infection. Locally produced IgG is the major antibody contributing to anti-WNV responses to infection in the vagina. The role of cellular immunity to protect animal against vaginal WNV infection was also examined in this study. The expression of major histocompatibility complex class II (MHC-II) molecules in the vaginal mucosa was upregulated after infection, which suggests the possibility that interferon-y (IFN-y) participates in the immune response, since MHC-11 expression is increased by IFN-Y· The infiltration of CD4 helper T cells (Th cells) and CD8 (cytotoxic lymphocytes [CTL]) in the vagina were also significant increased after infection.
These responses were coincident with a significant proliferation of CD4 and CD8 T cells from day 3 after infection. These results suggest IFN-y, CD4 T cells play an important role against WNV vaginal infection. ICAM-1, VCAM-1 and
CD44 adhesion molecules were involved in response to infection. Upregulation expression of ICAM-1 and CD44, and a de novo induction of VCAM-1 expression in the vagina were detected after virus infection, and these responses paralleled the infiltration of immune cells in the vagina.
Such responses were significantly accelerated and of greater magnitude in intravaginal (IVAG) immune, intraperitoneal (i.p.) immune and intradermal (i.d.) immune mice after intravaginal challenge with WNV, and this immunity completely protected animals against subsequent vaginal infection. Unexpectedly, the immune responses in i.d. immune mice were much stronger than IVGA immune mice. Moreover, there was a markedly higher CD4 and CD8 T cell infiltration and VCAM-1 expression in the vaginal mucosa, a significantly higher proliferation of CD4 and CD8 T cells in ILN, and a similar B220 B cell infiltration in the vagina and proliferation in the ILN. This suggests that i.d. immunization may be a possible route to induce immunity for prevention of vaginal viral infection.
The role of IL-5 in host immunity to vaginal WNV infection was investigated by using IL-5 gene knockout (GKO) mice. It was found that IL-5 GKO mice were more susceptible to WNV vaginal infection. Thus, infected cells could be detected in vagina epithelium earlier and remained for a longer duration than in normal control mice. The susceptibility of GKO mice to vaginal WNV infection correlated with delayed specific anti-WNV IgM and lgG antibodies in vaginal washings, lower numbers of IgG-containing plasma cell infiltrating the vagina, and a significantly lower B220 B cell and CD8 T cell infiltrate at certain time points compared normal control mice. However, a significant CD4 T cell infiltration and significant upregulation of expression of ICAM-1, VCAM-1 and MHC-II molecules in the vaginal mucosa at the later stage of infection, implies a compensatory mechanism may exist. The expression of IL-4 mRNA in the vaginal mucosa was enhanced after virus infection, coincident with the detection of specific anti-WNV lgG, suggesting that IL-4 contributed to specific antibody production and thus contributes to the eradication of WNV vaginal infection.
In this study, it was found that BALB/c mice are more susceptible to WNV vaginal infection than C57BL/6 mice, since the mortality to WNV vaginal infection in BALB/c mice was 10-fold higher than C57BL/6, and WNV-infected cells were detected in vaginal epithelium from day 2 to day 7 after infection in BALB/c mice, while these cells could only be detected on day 5 after infection in C57BL/6 mice. The susceptibility of BALB/c mice to WNV vaginal infection correlated with a markedly lower B220 B cell and CD8 T cell infiltration in the vagina of this strain
than in C57BL/6 mice. These results indicate that immune responses to vaginal WNV infection is genetically determined, varying in different mouse strains.
In a pilot experiment, the oestrogen-dominated model was used to compare immunity to intravaginal WNV infection in animals with a different hormonal status. Oestrogen-dominated mice were refractory to vaginal infection, but such resistance gave no protection against secondary virus challenge in the progesterone phase.
These mice presented a similar pattern of epithelial cell infection as progesterone dominated naive mice in primary infection, though the infiltration of B220 B cells and CD8 T cells in the vagina of these mice was higher than in progesterone dominated naive mice after infection, and the proliferation of total lymphocytes and CD8 T cells in ILN of these mice was also higher than in progesterone-dominated naive mice in the early course of the infection. Interestingly, the infiltration of CD4+ T cells in the vagina of virus-challenged progesterone phase immune mice was significant higher than oestrogen phase immune mice after rechallenge, and the proliferation of total lymphocytes, B220 B cells and CD8 T cells in ILN of the former was higher than latter at day 1 after challenge. These results suggest that the weaker and different profile of immunity initiated in the oestrogen phase does not produce full protection against secondary vaginal challenge.
The results from this study provides basic information about immune responses to vaginal virus infection and as such may contribute to the long-term development of vaccines to prevent the sexual transmission of viruses.
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Plume, Jeffrey Michael. "The role of viral strain in a congenital brain infection." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/2130.
Full textAbstract:
Lymphocytic Choriomeningitis Virus (LCMV) is a common arenavirus and natural murine pathogen that causes congenital neurodevelopmental disease in humans. Exposure to the virus in utero often results in severe and permanent damage the fetal brain and eyes. While usually severe, symptoms vary from case to case. Little is known about the pathological mechanism of congenital LCMV disease. Animal models of congenital LCMV infections suggest that timing of infection during gestation may influence disease outcomes; however, time alone cannot explain all of the variation observed in humans. Another possibility is that individuals are infected with different strains of LCMV.
The LCMV genome is composed of four highly conserved genes, yet even single amino acid mutations can cause the virus to exhibit very different properties in animal models. However, the role of viral strain in the context of neurodevelopment remains relatively unexplored. Here, using a rat model of congenital LCMV infection, we demonstrate that three related strains of LCMV produce different patterns of infection and disease states.
Infection with the highly neurotropic E350 strain induces a disease comparable to that observed in many confirmed cases of human congenital LCMV infection. While most of these animals survive to adulthood, they suffer permanent motor and behavioral abnormalities. Postmortem analyses of infected brains suggest that this strain has a proclivity for infecting mitotically active regions of the brain, including the cerebellum, olfactory bulb, hippocampus and subventricular region. E350 is not known to induce immunosuppression and viral clearance is likely mediated by a robust T-cell response. Indeed, we find high numbers of inflammatory cells in the brains of E350 animals and elevated pro-inflammatory cytokines and chemokines. The immune response, though responsible for the clearance of the virus from the brain, is also implicated in severe and sometimes permanent brain damage.
The Clone 13 strain, a strain typically associated with lymphatic tissue, readily infects the brains of developing rats. Many of these animals do not live to adulthood. Those that survive exhibit extreme stunted growth, but relatively normal neurodevelopment and little discernable neurological disease. By adulthood, the brains of these animals are comparable in size and structure to controls, despite reduced body mass. The Clone 13 infects the same brain regions as the E350, but is not cleared and remained at high titers for the duration of the study. Chronic infection is likely a consequence of the immunosuppressive effects of Clone 13 on the host immune system.
The WE2.2 causes a severe disease with both neurological and systemic symptoms. These animals exhibit persistent seizure like discharges during peak infection and significant motor deficits. They all fail to thrive, losing weight shortly after infection and die invariably 9-11 days post-inoculation. The brains of WE2.2 animals exhibit widespread infection of neurons in the cerebellum, hippocampus, olfactory bulbs, and cortex. WE2.2 does not cause immunosuppression and high levels of inflammatory cells are observed in the brain. Cytokine and chemokine expression is complex, without discernible trends and variable by brain region.
Finally, we looked at alpha-dystroglycan (α-DG) expression in the brain and compared it with infectivity among the strains. Alpha-dystroglycan is recognized as the principle receptor for LCMV and due to mutations in the viral glycoprotein, certain strains are more dependent on α-DG for infection. Several associations between α-DG expression and viral infectivity were observed; however α-DG expression alone could not explain all the differences in infection patterns.
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Lagache, Thibault. "Modeling the early steps of viral infection : a stochastic approach." Paris 6, 2009. http://www.theses.fr/2009PA066470.
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