The character of anti-hepatitis C virus T cell responses in HIV coinfection

Barrett, Lisa (2008) The character of anti-hepatitis C virus T cell responses in HIV coinfection. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

The human immune system has evolved to successfully eradicate most pathogens, however organisms such as hepatitis C virus (HCV) can circumvent the immune response and establish persistent infection in the majority of exposed individuals. While it is clear that broadly directed anti-HCV CD4⁺ and CD8⁺ T cell responses are important in spontaneous viral clearance, the immunologic correlates of persistent infection and treatment-associated viral clearance are markedly less well defined. There is conflicting data on how HCV modulates the immune system in monoinfection, and the data surrounding immunologic issues is even more limited in HIV coinfection. -- The type of immune cells that permit or facilitate persistent infection, as well as the character of the anti-HCV T cell response in the context of immunodeficiency and differential infectious outcomes, is unclear. The objective of this study was to assess potential mechanisms of immune modulation by HCV, delineate the types of cells that may be involved, and define anti-HCV T cell responses in the context of coinfection. -- In this work, we investigated whether HCV gene products induce interleukin-10 (IL-10), an immunomodulatory cytokine that facilitates chronic infection. We identified and phenotyped a novel cell population producing IL-10, not just in those infected with HCV, but in all healthy controls tested. IL-10 production by this new cell type may have a role in immune system homeostasis through immune regulation, but may also contribute to viral persistence. More of these previously undescribed cells produce IL-10 when exposed to HCV proteins, an effect that is accentuated when HCV-naive cells from HIV-infected individuals are exposed to HCV proteins. We demonstrated more robust anti-HCV T cell responses with viral clearance, and distinguished features of anti-HCV T cell responses associated with spontaneous versus treatment-induced clearance. We also described distinct HCV-specific T cell responses in HIV coinfection. Together, these findings emphasize the role of the immune system in HCV clearance, as well as in control of chronic infection, and illustrate the complex interactions between chronic pathogens in terms of their effects on the immune system.

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