Mechanisms of repeated control of acute hepatitis C infection in humans

 描述（由申请人提供）：总体而言，丙型肝炎病毒（HCV）在全球范围内慢性感染约1.85亿人，是肝衰竭和肝细胞癌的主要原因。随着口服干扰素保留HCV方案的出现，安全有效地治疗HCV感染变得更加容易。然而，单独治疗不太可能实现HCV控制。HCV感染者的识别具有挑战性，对于发病率最高的国家来说，治疗费用太高，治疗后可能发生再感染，耐药HCV的传播是可能的，即使治愈，治疗也不能完全逆转严重的肝损伤。在美国，青少年和年轻人中急性HCV感染的流行率不断上升，这使得预防性疫苗开发工作变得更加紧迫。然而，疫苗开发仍然面临许多挑战，包括候选疫苗可以测试的人群有限，HCV的巨大序列多样性以及对介导保护性免疫的不完全理解。对HCV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，需要更多的研究来确定免疫力的明确相关性，以评估健康志愿者。这项拟议研究的总体目标是通过研究反复接触和控制HCV的人来定义先天，体液和T细胞反应，这些反应允许对最广泛的丙型肝炎病毒感染的保护性免疫。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，以帮助选择增强诱导保护性反应的疫苗佐剂。HCV的序列将在诱导适应性免疫应答之前和之后进行比较，以更好地了解具有显着序列多样性的病毒如何能够逃避免疫应答。获得的关于对HCV的体液应答的知识将用于设计疫苗以引发中和HCV感染的抗体。了解保护性T细胞反应将有助于创造一种疫苗，诱导T细胞能够清除感染任何病毒的细胞，这些病毒逃避前线中和抗体。总之，我们预计，拟议的研究研究反复暴露，但不发展为持续性HCV感染的人将定义相关的保护性免疫疫苗设计的目标。

 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.