Hepatitis C virus (HCV) infects over 170 million people world-wide, causing a spectrum of liver disease ranging from an asymptomatic carrier state to end-stage liver disease. HCV efficiently escapes host immune responses and establishes persistence in >80% of acute cases;however the mechanism is poorly understood. Antiviral therapy with interferon (IFN)-a and ribavirin clears HCV infection in about half of those patients treated, but there is a large variation in IFN-a based treatment efficacy depending on the viral genotype. High viral genetic variation is associated with success of therapy. Persistent HCV infection is associated with hypergammaglobulinemia, high levels of antiviral antibody, circulating immune complexes, and immune complex disease. Infection of immortalized human hepatocytes (IHH) with cell culture grown HCV induces IFN expression, although virus replication is not inhibited. Modest HCV neutralizing antibody response is generated in humans from natural infection, and neutralization can be augmented in vitro by serum complement. Based on these observations, we hypothesize that HCV proteins interact with cellular proteins to promote escape from innate immunity. We will undertake an in-depth investigation of the molecular interactions of HCV or specific HCV proteins and components of the innate immune response.
Aim 1 will identify host factors involved in HCV mediated modulation of IFN signaling pathway.
Aim 2 will measure the effects of HCV genetic variation on the evasion of IFN-a responses.
Aim 3 will investigate the molecular mechanisms for HCV induced complement regulation. Studies will be performed using HCV cDNA from patient samples, replicon, and cell culture grown HCV. Together, these studies will improve our understanding of how viral infections interfere with innate immune responses to promote viral persistence, and will provide future avenues for therapeutic modalities.

Public Health Relevance

Hepatitis C virus (HCV) infects a large number of people world-wide, causing a spectrum of liver disease, including cirrhosis and hepatocellular carcinoma. We will undertake an in-depth investigation in understanding how HCV infection interferes with the innate immune responses to promote viral persistence, and to provide future avenues for therapeutic modalities.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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Washington University
Saint Louis
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