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Contribution of guanine nucleotide binding protein beta polypeptide 3 (GNB3) and lymphocyte activation gene 3 (LAG-3) to HIV susceptibility and immune dysfunction

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dc.contributor.supervisor Fowke, Keith (Medical Microbiology) en_US
dc.contributor.author Juno, Jennifer
dc.date.accessioned 2014-09-02T20:21:38Z
dc.date.available 2014-09-02T20:21:38Z
dc.date.issued 2010 en_US
dc.date.issued 2012 en_US
dc.date.issued 2012 en_US
dc.identifier.citation Juno JA et al, AIDS Rev., 2010, 12(3):164-76 en_US
dc.identifier.citation Juno JA et al, Plos Pathogens, 2012, 8(8):e1002838 en_US
dc.identifier.citation Juno JA et al, Retrovirology, 2012, 9:1 en_US
dc.identifier.uri http://hdl.handle.net/1993/23948
dc.description.abstract Host genetics play an important role in regulating susceptibility to infectious diseases, including the human immunodeficiency virus (HIV). A polymorphism in a G protein signaling gene (GNB3) previously associated with rapid HIV disease progression is found at high frequencies among African populations, yet its impact on HIV acquisition and disease progression is unknown. The GNB3 gene is located on chromosome 12 near the CD4 gene, as well the gene encoding the regulatory protein lymphocyte activation gene 3 (LAG-3). The goal of this thesis was to characterize the impact of GNB3 genotype on risk of HIV acquisition and disease progression, as well as the relevance of LAG-3 expression to immune exhaustion during HIV infection. Because G proteins are involved in HIV entry and replication in T cells, polymorphisms affecting G protein signaling, such as GNB3 C825T, could dramatically alter susceptibility to HIV infection, viral replication and rates of disease progression. Similarly, the expression of the inhibitory protein LAG-3 could, like other exhaustion markers, mediate increasing immune dysfunction during chronic infection. Both GNB3 and LAG-3 could represent targets for therapeutic intervention to slow disease progression or restore lymphocyte function among HIV-infected individuals. Surprisingly, our studies showed that GNB3 genotype was not associated with the risk of HIV acquisition in either a female sex worker or perinatal transmission cohort. Disease progression and immune activation among healthy and HIV-infected women were also independent of GNB3 genotype. While the RNA splicing events typically associated with the presence of the GNB3 825T allele could not be detected among cohort participants, ii differences in LAG-3 expression were observed between women of differing GNB3 genotypes. In this cohort, LAG-3 expression on T cells, NK cells and iNKT cells in the peripheral blood was significantly increased among HIV+ women compared to healthy controls, and was not decreased by antiretroviral therapy. The increase in LAG-3 expression was greatest on NK and iNKT cells, an innate lymphocyte subset capable of rapid and robust cytokine production upon stimulation with CD1d-restricted lipid ligands. Lymphocytes derived from the female genital mucosa, the site of HIV acquisition in the female sex worker cohort, expressed significantly higher levels of LAG-3 compared to peripheral blood, suggesting a role for LAG-3 in regulating mucosal immunity, particularly on double negative (CD4-CD8-) T cells. Finally, we demonstrated that iNKT cells derived from HIV-infected women exhibited significantly lower IFN production compared to healthy controls upon lipid stimulation, which inversely correlated with iNKT LAG-3 expression. Lipid stimulation of PBMC from HIV+ and ARV-treated women also demonstrated perturbations in the secretion of multiple cytokines and chemokines, suggesting that iNKT function is not restored following ART. Together, these data imply that LAG-3 may play an important role in regulating iNKT function during chronic HIV infection. Blocking LAG-3 signaling could therefore restore components of innate immunity that are not improved by current ART, as well as alter HIV susceptibility at the female genital tract, making LAG-3 an attractive target for future therapeutics and viral eradication strategies. en_US
dc.publisher Permanyer en_US
dc.publisher PLoS en_US
dc.publisher Retrovirology en_US
dc.subject HIV en_US
dc.subject Immunology en_US
dc.title Contribution of guanine nucleotide binding protein beta polypeptide 3 (GNB3) and lymphocyte activation gene 3 (LAG-3) to HIV susceptibility and immune dysfunction en_US
dc.degree.discipline Medical Microbiology en_US
dc.contributor.examiningcommittee Yang, Xi (Medical Microbiology) Marshall, Aaron (Immunology) Bernard, Nicole (McGill University) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note October 2014 en_US


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