Immunity of neoantigen response in HCV, HIV, and HCV-HIV

描述（由申请人提供）：丙型肝炎病毒（HCV）是美国最常见的慢性病毒性肝炎病因。根据艾滋病毒传播途径的不同，9%-80%的艾滋病毒感染者合并感染丙型肝炎病毒。HIV感染似乎改变了HCV相关疾病的病程，加速了向肝硬化发展的速度。尽管HCV-HIV合并感染的流行率很高，但这些病毒之间的相互关系尚未得到很好的了解。我们认为，监测免疫反应提供了一个独特的和可控的机会，以评估在体内的免疫功能在人体系统。在这方面，HCV和HIV感染者对新抗原疫苗的反应性受损。无论是丙型肝炎病毒还是艾滋病毒感染都会导致常见或独特的缺陷。细胞、抗原呈递细胞（ARC）或B细胞功能是导致新抗原反应受损的原因尚不清楚。外周循环未成熟树突状细胞（DC）亚群（MDC和PDC或髓细胞和浆细胞样DC）已成为形成T细胞免疫的关键ARC。我们和其他人已经证明，在HCV和HIV感染中，DC功能都受到损害，但两者的损害程度大不相同。我们还发现，在HIV感染中，原生T细胞扩增能力受损，这种功能障碍预示着对新抗原疫苗的反应。这种扰动是否存在和/或与HCV感染的新抗原反应性有关尚不清楚。本课题将利用该模型在DC、B细胞和T细胞频率/功能水平上探讨HCV、HIV和HCV-HIV感染中疫苗反应性降低的机制。目的将是表征HCV， HIV和HCV-HIV感染宿主保护性免疫的形成，并为这些慢性感染的新免疫治疗策略的发展提供见解。

DESCRIPTION (provided by applicant): 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.