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）是美国慢性病毒性肝炎最常见的病因。根据HIV传播途径的不同，9%-80%的HIV感染者同时感染HCV。HIV感染似乎会改变HCV相关疾病的病程，加速进展为肝硬化的速度。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理解。我们建议，监测免疫反应提供了一个独特的和控制的机会，以评估在人体系统的体内免疫功能。在这方面，对新抗原疫苗的反应性在HCV和HIV感染个体中均受损。无论是HCV还是HIV感染都导致了共同或独特的缺陷。细胞、抗原呈递细胞（ARC）或B细胞功能是导致受损的新抗原应答的原因尚不清楚。外周循环未成熟树突状细胞（DC）亚群（MDC和PDC或髓样和浆细胞样DC）已成为形成T细胞免疫的关键ARC。我们和其他人已经表明，DC功能在HCV和HIV感染中均受损，并且每种感染的受损程度都有很大不同。此外，我们还表明，HIV感染中的naTve T细胞扩增能力受损，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HCV感染中的新抗原反应性有关尚不清楚。目前的提案将使用该模型在DC、B细胞和T细胞频率/功能水平上探索HCV、HIV和HCV-HIV感染中疫苗应答性降低的机制。我们的目标将是在HCV，HIV和HCV-HIV感染的宿主中形成保护性免疫的特征，并为这些慢性感染的新免疫策略的开发提供见解。

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.