Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular cancer. Only a minority of infected persons resolve the infection with most developing chronic infection, interventions with drug therapies have only been partially successful in ameliorating disease, therefore effective vaccine development is essential. Accumulating evidence points towards anti-viral CD4+ and CD8+ T cell responses as critical in the control of HCV replication and associated disease. My laboratory has demonstrated a highly effective way to induce human anti-viral CTLs. By presenting antigens on dendritic cells [DC], """"""""nature's adjuvant"""""""", one can elicit strong, CD4+ and CD8+, T cell immunity that is durable for several years. We propose to adapt this technology to boost T cell responses in chronically infected chimpanzees, the only other can be generated species known to support HCV replication.
The first aim will determine whether mature DCs can be generated from mononuclear precursors of chronically infected chimpanzee, and whether they exhibit effective antigen presenting capacity.
The second aim will assess whether DCs pulsed with HCV proteins can restore deficient CD4+ and CD8+ T cell responses in chronically infected animals. Because depletion of CD4+ T cells in animals who have controlled infection leads to viremia, the expectation is that restoration of HCV-specific CD4+ responses will reinstate the CD8+ immune response. In the third aim we will explore a unique approach to target HCV antigens to DCs which does not require the prior identification or isolation of immunogenic epitopes or proteins, namely amplification of RNA encoding selected areas of the HCV genome, and transfection of DCs via electroporation. The approach will first be optimized in vitro for HCV antigens, after which we will test the efficacy of RNA-transfected DCs to induce T cell immunity in vivo in chronically infected chimpanzees. Through the use of DC-based, HCV directed clinical studies, more information will be gained to optimize a new modality of active immunotherapy.
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