Mechanisms of repeated control of acute hepatitis C infection in humans

 描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)慢性感染全球约1.85亿人，是导致肝功能衰竭和肝细胞癌的主要原因。随着口服、不使用干扰素的丙型肝炎病毒治疗方案的出现，安全有效地治疗丙型肝炎病毒感染变得容易得多。然而，仅靠治疗不太可能实现丙型肝炎病毒的控制。丙型肝炎病毒感染者的识别具有挑战性，治疗对于发病率最高的国家来说过于昂贵，治疗后可能发生再感染，抗药性丙型肝炎病毒的传播是可能的，即使治愈，治疗也不能完全扭转严重的肝脏损害。在美国，急性丙型肝炎病毒感染在青少年和年轻人中的流行正在上升，这给预防性疫苗的开发工作带来了新的紧迫性。然而，疫苗开发仍然面临许多挑战，包括可以测试候选疫苗的人群有限，丙型肝炎病毒序列的巨大多样性，以及对介导保护性免疫的因素的不完全了解。对丙型肝炎病毒免疫应答的研究为保护性免疫提供了重要的见解。然而，在候选疫苗在有限的高危人群中进行测试之前，还需要更多的研究来确定明确的免疫相关性，以便在健康志愿者中进行评估。这项拟议研究的总体目标是通过研究反复接触和控制丙型肝炎病毒的人，确定先天、体液和T细胞反应，从而对最广泛的感染丙型肝炎病毒产生保护性免疫。这项研究将包括对感染的最早先天反应以及下游适应性反应的评估，以帮助选择增强保护性反应诱导的疫苗佐剂。丙型肝炎病毒的序列将在诱导适应性免疫反应之前和之后进行比较，以更好地了解这种具有显著序列多样性的病毒如何能够逃避免疫反应。有关丙型肝炎病毒体液反应的知识将被用于设计疫苗，以诱导中和丙型肝炎病毒感染的抗体。了解保护性T细胞反应将促进疫苗的创造，这种疫苗能够诱导T细胞清除感染了任何病毒的细胞，从而逃避前线中和抗体。总而言之，我们预计，拟议的研究将对反复暴露但没有发展成持续性丙型肝炎病毒感染的人进行研究，这将在疫苗设计中确定保护性免疫与靶标的相关性。

 DESCRIPTION (provided by applicant): Overall Hepatitis C Virus (HCV) chronically infects ~185 million people worldwide and is a major cause of liver failure and hepatocellular carcinoma. With the advent of oral, interferon-sparing HCV regimens, it has become much easier to safely and effectively treat HCV infection. However, HCV control is not likely to be achieved with treatment alone. Identification of those with HCV infection is challenging, therapies are too costly for countries with the highest incidence, reinfection can occur following treatment, transmission of drug-resistant HCV is possible, and treatment does not fully reverse severe liver damage even when cure is achieved. There is a rising epidemic of acute HCV infection in adolescents and young adults in the United States that gives new urgency to prophylactic vaccine development efforts. However, numerous challenges for vaccine development remain, including limited populations in which candidate vaccines can be tested, the enormous sequence diversity of HCV, and incomplete understanding of what mediates protective immunity. The study of immune responses to HCV has provided important insight into protective immunity. However, more research is needed to identify clear correlates of immunity to assess in healthy volunteers before candidate vaccines are tested in the limited at-risk populations available. The overall goal of this proposed research is to define the innate, humoral, and T cell responses that allow protective immunity against the broadest array of infecting hepatitis C viruses by studying people who are repeatedly exposed to and control HCV. This research will include an assessment of the earliest innate response to infection as well as the downstream adaptive response to help select a vaccine adjuvant that enhances induction of protective responses. The sequence of HCV will be compared before and after induction of adaptive immune responses to better understand how the virus, with its remarkable sequence diversity, is able to evade immune responses. The knowledge gained about humoral responses to HCV will be used to design vaccines to elicit antibodies that neutralize HCV infection. Understanding protective T cell responses will enhance creation of a vaccine that induces T cells capable of clearing cells infected with any virus that evades the frontline neutralizing antibodies. In sum, we anticipate that the proposed research studying people who are repeatedly exposed but don't develop persistent HCV infection will define correlates of protective immunity to target in vaccine design.