Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States. Between 9% and 80% of HIV infected individuals are coinfected with HCV. HIV infection appears to alter the course of HCV related disease, accelerating rates of progression to cirrhosis. Despite a high prevalence of HCV-HIV coinfection, the interrelationships between these viruses are not well understood. Peripherally circulating immature dendritic cell (DC) subpopulations (MDC and PDC or myeloid and plasmacytoid DC) have emerged as key ARC in shaping T cell immunity. Dysfunction in these populations has been shown in HIV infection and dysfunction in in-vitro expanded monocyte derived MDC has been shown in HCV infection. Our data using """"""""viral-relevant"""""""" TLR ligands as stimulants in direct ex-vivo assays with freshly prepared, nonexpanded cell populations reveal a predominant deficit of PDC IFN-alpha secreting function in HCV infection, whereas we observe a predominant deficit of non-PDC IFN-alpha secreting function in HIV infection. In HCV-HIV coinfected subjects both functions are impaired. Furthermore, we observe defects in MDC IL-12 secreting function in both HCV and HIV infection. This data indicates DC function is impaired in both chronic viral infections, with the impairment quite different in each. Further preliminary data indicates that impaired TLR ligand induced DC function present in HCV and HIV infection results in impaired DC-NK interactions, resulting in reduced DC mediated NK function. The goal of these studies will be to characterize MDC-NK interactions in the HCV and HCV-HIV infected host. We will explore the hypothesis that MDC function is differentially altered as a consequence of HCV vs. HIV infection, with differential impairment in ability to secrete immune regulatory cytokines, including IFN-alpha and IL-12. These abnormalities in DC function are hypothesized to result in impaired activation of NK cells that in turn prevents control of the infection. To address this hypothesis we will determine the impact of HCV, HIV, and HCV-HIV infection on MDC ability to activate NK cells to proliferate, secrete cytokine, secrete chemokine and secrete cytotoxic granule protein; identify NK cell subset(s) activated by MDC; and identify soluble and cell-cell contact factors necessary for the MDC-NK interaction in healthy controls vs. HCV, HIV, and HCV-HIV infected subjects.
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