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HIV-Hepatitis C Virus Interactions and Pathogenesis


Biography

Overview
Because of their shared routes of transmission, HCV coinfection with HIV is remarkably frequent in the U.S., particularly among injection drug users (IDU). With the success of HAART, traditional opportunistic infections among HIV-infected persons have been replaced by end stage liver disease due to viral hepatitis, particularly HCV. The most important clinical features of HCV in HIV-infected persons compared to HIV- negative persons are (1) its higher rates of persistence;(2) low rates of response to interferon (IFN) based antiviral therapy;and (3) accelerated hepatic fibrosis progression. Using cell-based models of HCV replication, we have recently shown that STAT1 is the principal innate antiviral component against HCV. We further demonstrated that HCV selectively degrades STAT1 and impairs type I IFN signaling in a proteasome-dependent manner. This action is mediated through the interaction of HCV core protein with STAT1. We have observed that recombinant HIV gp120 enhances HCV production in an HCV replicon model and impairs type I IFN signaling. Finally, we have demonstrated that HCV core and NS5A directly upregulate TGF-beta1, the principal fibrogenic cytokine. We hypothesize that HIV augments HCV's suppressive effects on IFN signal transduction and that it promotes HCV's effects on TGF-beta1 in the liver. We propose to: (1) define the mechanism of HIV's proviral effect on HCV replication and (2) characterize the effect of HIV on HCV regulation of TGF-beta1 in the liver. For Aim 1, we will (a) characterize the effect of gp120 on HCV-induced STAT1 degradation and suppression of IFN signaling;(b) determine whether gp120's proviral effects on HCV are reversed by restoration of type I IFN signaling;(c) evaluate the signaling mechanism by which gp120 regulates HCV replication;and (d) assess the effect of gp120 on IFN-stimulated genes and upstream genes. For Aim 2, we will (a) define how HCV regulates TGF-beta1 expression in hepatocyte-derived cell lines;(b) determine whether gp120 independently regulates TGF-beta1 expression in hepatocytes;(c) determine how gp120 modifies HCV regulation of TGF-beta1 expression in HCV replication models;and (d) determine whether gp120 enhances fibrogenic signals released by hepatocytes harboring HCV. These studies will shed considerable light on HIV-HCV pathogenic interactions and offer a means of productively disrupting these interactions.

R01AI069939
CHUNG, RAYMOND T

Time
2006-07-01
2012-06-30
Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.