This study will define host and immune factors that influence HCV and HIV-1 infection. Understanding the immunopathogenesis of HIV-1 is vital to vaccine development and the establishment of new treatment strategies. In addition, HCV infection is recognized as a major worldwide threat with significant implications for HIV-1-coinfected individuals.
The specific aims of this application are: 1) to investigate the role of viral specific immunologic responses in controlling HIV-1 and HCV infection, 2) to investigate the relationship between CD4+ and CD8+ cellular activation with HIV-1 viral load, HCV viral load, and HIV-1 clinical progression, 3) to investigate how host genetic factors that modulate the expression of intracellular cytokines affect the levels of HCV RNA, HIV-1 RNA and HIV-1 clinical progression, and 4) to investigate the mechanism by which HCV infection affects HIV-1 clinical progression. This study will utilize biologic specimens stored from participants in the Hemophilia Growth and Development Study (HGDS), a U.S. multi-center natural history study that enrolled subjects between 1989 and 1990 with 7-8 years of follow-up. The HGDS included those who were HCV infected (n=126) and those HIV-1/HCV co-infected (n=207).
The first aim will utilize tetramer and ELlSPOT assays on longitudinally collected specimens to determine the relationship between HIV-1 specific responses and the control of viral replication and clinical progression. Similar studies will be performed to test the relationship between HCV-specific responses and HCV viral load in both cohorts.
The second aim will determine if cellular activation, as measured by expression of activation markers on longitudinally collected CD4+ and CD8+ cells, is associated with HIV-1 and HCV RNA levels, as well as HIV-1 clinical progression.
The third aim will determine if genetic polymorphisms in the promoter region of various Th1 and Th2 cytokines predicts HIV-1 clinical progression, and/or the quantity of inducible intracellular cytokines.
The final aim of this study will explore the mechanism underlying recent observations that HCV infection and viral load adversely affect HIV-1 clinical progression. Two potential explanations for these observations will be tested. First, to determine if systemic cellular activation, that may occur in the setting of chronic HCV replication, accounts for the enhanced risk of HIV-1 progression, after controlling for CD4+ cell number and HIV viral load. Second, to explore the possibility that chronic HCV infection, previously shown to occur in the setting of waning HCV-specific immune responses, is associated with down-regulation of HIV-1 specific cellular responses and clinical progression. This study will utilize state-of-the-art technology in a well-characterized cohort to expand the current understanding of host and immune factors that influence viral replication and clinical disease progression.
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