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

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)是美国慢性病毒性肝炎最常见的原因。根据艾滋病毒的传播途径，9%-80%的艾滋病毒感染者与丙型肝炎病毒合并感染。HIV感染似乎改变了丙型肝炎病毒相关疾病的进程，加速了进展为肝硬变的速度。尽管丙型肝炎病毒和艾滋病毒混合感染的发病率很高，但这些病毒之间的相互关系尚不清楚。我们认为，对免疫反应的监测提供了一个独特的、可控的机会来评估人体系统的体内免疫功能。在这方面，丙型肝炎病毒和艾滋病病毒感染者对新抗原疫苗的反应性都受到了损害。丙型肝炎病毒或艾滋病病毒感染是否会导致常见或独特的缺陷。导致新抗原反应受损的细胞、抗原提呈细胞(ARC)或B细胞功能尚不清楚。外周循环中的未成熟树突状细胞(DC)亚群(MDC和PDC或髓系和浆细胞样树突状细胞)已成为形成T细胞免疫的关键ARC。我们和其他人已经证明，在丙型肝炎病毒和艾滋病病毒感染中，DC功能都受到了损害，但两者的损害情况截然不同。此外，我们还表明，在HIV感染中，NATve T细胞的扩张能力受到损害，并且这种功能障碍预测了对新抗原疫苗的反应。这种扰动是否存在和/或与丙型肝炎病毒感染中的新抗原反应性有关尚不清楚。目前的建议将利用这一模型从DC、B细胞和T细胞频率/功能的水平上探讨丙型肝炎病毒、艾滋病病毒和丙型肝炎病毒-艾滋病病毒感染中疫苗应答降低的机制。其目的将是表征丙型肝炎病毒、艾滋病毒和丙型肝炎病毒感染宿主中保护性免疫的形成，并为开发针对这些慢性感染的新的免疫治疗策略提供洞察力。

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.