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Evaluating T-cell Immunity in HCV/HIV Co-infection

Due to shared routes of transmission, co-infection with Hepatitis C (HCV) and Human Immuno-deficiency Virus (HIV) has become prevalent worldwide, with approximately one-third of all HIV-infected individuals and about 10% of all HCV infected individuals in North America being co-infected with the other virus (1). Recent advances in HIV treatment have increased the life expectancy of HIV-infected patients, resulting in HCV-associated disease to develop into a major cause of morbidity and mortality among the co-infected population. HIV is consistently shown to have a negative effect on different aspects of HCV disease, from increased HCV RNA levels (2) to aggravated liver fibrosis and more rapid progression to cirrhosis and end-stage liver disease (3). The host immune responses play a major role in not only controlling HCV infection, but also in causing hepatic inflammation and damage. Despite major advances in the understanding of the pathogenesis of these two infections, the mechanisms underlying the role of immune responses in more rapid progression of HCV disease in HCV/HIV co-infection is not quite clear.
This thesis is generated based on an investigation to understand why HIV infection worsens HCV pathogenesis. This question is addressed throughout this thesis from different immunological aspects, with a focus on the function of T-cells. I have demonstrated that in HCV/HIV co-infection, functional HIV-specific T-cells accumulate in the liver and produce an array of cytokines, including INF- and TNF-, which may represent a bystander role for HIV in the aggravation of HCV-induced liver damage. My data also demonstrate that co-expression of two defined T-cell exhaustion markers, Tim-3 and PD-1 may play a significant role in HCV-specific T-cell dysfunction, in the setting of HIV co-infection. Both total and HCV-specific peripheral T-cells co-express Tim-3 and PD-1 in significantly higher frequencies, compared to HCV mono-infection. In co-infection, HCV-specific CD8+ T-cells showed greater frequencies of Tim-3/PD-1 dual-expression than those being HIV-specific, indicating a greater degree of exhaustion in the former. Additionally, I demonstrated that some HIV mono-infected individuals may contain CD8+ T-cells that cross-recognize two defined HLA-A2-restricted epitopes within the HIV and HCV proteome, the HIV-Gag: SLYNTVATL and HCV-NS5b: ALYDVVSKL. This T-cell cross-reactivity was further elaborated in the context of HCV/HIV co-infection, demonstrating that degeneracy of HIV-specific T-cells may play a role in the immuno-pathology of co-infection.
Altogether, these data could be integrated into the foundation of potential mechanisms involved in the immunopathogenesis of HCV/HIV co-infection, and be applied to further investigation in basic science and clinical studies in this field.

Identiferoai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/29898
Date31 August 2011
CreatorsVali, Bahareh
ContributorsOstrowski, Mario
Source SetsLibrary and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada
Languageen_ca
Detected LanguageEnglish
TypeThesis

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