One of our research interests is hepatitis C virus infection. More than 4 million subjects in the US and more than 120 million worldwide are infected with the hepatitis C virus (HCV), and complications arising from chronic HCV infection are the most common causes for liver transplantation in Western countries. A vaccine to prevent HCV infection does not exist and about half of the chronically infected patients do not respond to the current therapy. HCV is an enveloped, positive-stranded RNA virus with extensive genetic heterogeneity. Its astonishing propensity to cause persistent infections in otherwise immunocompetent adults has prompted extensive research. A major emphasis of our program has been the identification of immunological correlates of recovery from hepatitis C and the analysis of mechanisms of viral immune evasion.
An important early finding was the discovery that HCV-specific T cells remain readily detectable for decades in the blood after recovery from infection whereas HCV-specific antibodies may disappear entirely (Nature Medicine 2000; 6:578-582). We proceeded with a detailed comparison of HCV-specific T cells in HCV-recovered and persistently infected patients and demonstrated along with others in the chimpanzee model that spontaneous recovery from infection may result in T cell based protective immunity upon secondary HCV rechallenge.
While the importance of T cell responses in the clearance of HCV is now well accepted, it remains unknown why only 20-30% of patients mount a successful T cell response and recover spontaneously. To address this question we are studying the role of innate immune cells in the early antiviral response and the induction and regulation of subsequent adaptive immune responses against HCV. We are also collaborating with geneticists and epidemiologists to assess the functional impact of genetic variants that affect the outcome and disease progression of hepatitis C.
An equally important issue is the role of innate and adaptive immune responses in chronic hepatitis C and disease progression. The incidence of complications from chronic liver disease, such as cirrhosis and hepatocellular carcinoma, is projected to increase over the next 20 years, possibly reaching the same incidence as in Japan where wide-spread distribution of HCV occurred decades earlier than in Western countries. We therefore study innate and adaptive immune responses in chronic liver disease and hepatocarcinoma and evaluate strategies for immune modulation and immunotherapy.