This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Coinfection of hepatiitis C virus (HCV) with human immunodeficiency virus (HIV) occurs in 20-30% of HIV infected patients. Patients with HCV/HIV coinfection tend to have higher HCV viral loads than controls. Furthermore, there is now evidence that initiation of effective antiretroviral therapy (ART) may be associated with paradoxical increases in HCV viral load. HCV viral flare may be associated with increases in serum tranaminases which affect clinical decision making, vis a vis discontinuation of ART. Previous studies have failed to prospectively evaluate these issues in a systematic, progressive manner. The mechanisms responsible for viral load increase during effective immune reconstitution have also not undergone detailed evaluation. We propose the following Specific Aims to address these issues: 1. To develop and perform a clinical intervention trial in HCV/HIV coinfected subjects treated with ART in order to characterize early/late HCV viral kinetics as well as the prevalence, significance, and pathogenesis of HCV viral load increase. 2. To prospectively evaluate the significance and role of HCV quasispecies emergence following ART initiation between treatment responders and nonresponders. 3. To define immunologic correlates during immune reconstitution that are associated with development of increased HCV viral load and/or liver injury. We will test specific, hypothesis-driven questions to help achieve the broader goals described within our Specific Aims. In an effort to develop a conceptual framework for the relationship between hepatitis C infection and HIV, we will use the tools of mathematical modeling, molecular epidemiology and immunology to study viral selection, mutation and replication.
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