Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States. Depending on route of HIV transmission, 9%-80% of HIV infected individuals are coinfected with HCV. HIV infection appears to alter the course of HCV related disease, accelerating rates of progression to cirrhosis. Despite a high prevalence of HCV-HIV coinfection, the interrelationships between these viruses are not well understood. We propose that monitoring of immunization response provides a unique and controlled opportunity to evaluate in vivo immune function in the human system. In this regard, responsiveness to neoantigen vaccine is impaired in both HCV and HIV infected individuals. Whether HCV or HIV infection contribute to common or unique defects in. cell, antigen presenting cell (ARC), or B cell function that are responsible for the impaired neoantigen response is not known. Peripheral circulating immature dendritic cell (DC) subpopulations (MDC and PDC or myeloid and plasmacytoid DC) have emerged as key ARC in shaping T cell immunity. We, and others, have shown that DC function is impaired in both HCV and HIV infection, with the impairment quite different in each. We additionally have shown that naTve T cell expansion capacity is impaired in HIV infection, and that this dysfunction predicts response to neoantigen vaccine. Whether this perturbation exists and/or relates to neoantigen responsiveness in HCV infection is not known. The current proposal will use this model to explore the mechanism of reduced vaccine responsiveness in HCV, HIV and HCV-HIV infection at the level of DC, B cell and T cell frequency/function. The goal will be to characterize the formation of protective immunity in the HCV, HIV and HCV-HIV infected host, and provide insight for the development of new immunotherapeutic strategies for these chronic infections.
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