Keywords: virus, protective immunity, hepatitis C virus, T cell, vaccine, immunotherapy
Our laboratory investigates the host immune response to chronic human viral infections, particularly HIV and hepatitis C virus (HCV). HCV infects nearly 200 million people worldwide, resulting in chronic infection in about 75% of cases. We examine the role of the immune response in clearance of HCV upon exposure to this virus by studying responses to HCV from the earliest phases of infection through years following infection in a longitudinal, prospective cohort of people at risk of HCV infection. This allows a comparison of the innate, humoral, and cellular immune responses to infection with clearance versus persistence. We have demonstrated that spontaneous control of HCV does not uniformly generate sterilizing immunity, but reinfection is associated with a reduction in the magnitude and duration of viremia (compared with the initial infection), broadened cellular immune responses, and generation of cross-reactive humoral responses. These findings are consistent with development of adaptive immunity that is not sterilizing but protects against chronic disease. To identify mechanisms of protective immunity against HCV infection and improve prophylactic HCV vaccine design, we are determining the cellular and humoral responses associated with repeated HCV control. A significant barrier to the development of an HCV vaccine is that HCV is a highly diverse virus. Our laboratory has also developed and evaluated methods of HCV vaccine design that may overcome this diversity and stimulate an effective immune response.
We have demonstrated that the development of HCV-specific T cell clones is likely arrested during the first year of infection and that molecular phenotypes associated with this loss of functional activity vary based on whether lymphocytes recognize epitopes that do or do not undergo substitution. One of the molecules upregulated on T cells chronically stimulated with antigen in chronic viral infections and in cancer is programmed death-1 (PD-1), which reduces T cell activity when it binds ligand. Blockade of PD-1 activates T cells specific for tumor or viral antigens. Having already demonstrated that upregulation of PD-1 requires maintenance of intact antigen in HCV infection, we have recently identified a novel means through which tumors and chronic viral infections induce PD-1 expression.
More recently, our lab has become interested in activation of an innate sensing system, the inflammasome, which induces antiviral cytokines as well as inflammation. We have defined the mechanism through which both HIV and HCV activate the inflammasome and novel mechanisms through which inflammasome activation is suppressed.
SciVal Profile: Publications and Interests