IMMUNOLOGICAL STRATEGIES FOR CURING CHRONIC HEPATITIS VIRUS INFECTIONS

Emory University, Atlanta GA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hepatitis C virus (HCV) establishes chronic infection in the liver of nearly 80% of those infected and in addition to causing hepatitis, may cause liver cirrhosis and hepatocellular carcinoma. These detrimental long-term sequelae of persistent HCV infection now comprise the leading indication for liver transplantation in the United States. Defining the elements of the immune response that fail or are insufficient to mediate HCV infection resolution in the majority of those infected is critical for advancing our understanding of how to therapeutically intervene in HCV disease pathogenesis and is the focus of our work. We have aimed to characterize phenotypic and functional differences of HCV-specific T cells with a focus on co-inhibitory molecules such as PD-1. Initial studies are focused on characterizing the baseline immune responses present in the chimpanzee cohort prior to administration of the therapeutic antibodies. This work recently resulted in a publication showing an exhausted phenotype with high PD-1 expression on liver infiltrating HCV-specific lymphocytes in chronic HCV infected patients. Access to a chronically infected patient cohort in whom liver biopsy tissue is available represents a great resource for studies characterizing the role of co-inhibitory molecules in HCV pathogenesis. Functional studies show enhanced proliferative capacity with blockade of the PD-1/PD-L1 interaction. Further, we have also demonstrated that HCV specific T cells undergo massive apoptosis during HCV infection. These data provide further support and excitement for the forthcoming therapeutic studies.