Humoral Immune Response to Acute HCV Infection

项目2的主要目的是通过检查有效中和抗体应答的临床和分子相关性来扩展我们对急性丙型肝炎病毒（HCV）感染的体液免疫应答的研究。我们最近已经证明，抗HCV中和抗体驱动的演变，HCV蛋白E1和E2在急性感染，表明中和抗体在体外检测能够降低体内病毒的健身。此外，急性感染的现有证据表明，高滴度中和抗体反应存在于继续清除病毒血症的人中，而不是进展为慢性的人中。我们假设中和抗体是一个预测性的清除标记， 急性HCV感染，并且逃避这些应答是病毒持续存在的一种受限制的机制。因此，我们提出了以下目标，以阐明临床效用和基本机制的HCV中和：（I）定义一个有效的抗-HCV中和抗体反应的阳性预测值作为一个预测清除急性感染期间，和（II）调查的机制，HCV逃避中和抗体反应在急性感染期间。项目1的细胞免疫应答研究结果将被整合，以扩大人类对HCV的体液和细胞免疫应答之间相互作用的知识。我们已经证明，我们可以获得本研究所需的关键标本，并将能够对从急性感染过渡到确诊感染的人群的适应性免疫反应进行独特的纵向研究。

The primary objective of Project 2 is to expand on our studies of humoral immune response to acute hepatitis C virus (HCV) infection by examining the clinical and molecular correlates of potent neutralizing antibody responses. We have recently demonstrated that anti-HCV neutralizing antibodies drive the evolution of HCV proteins E1 and E2 during acute infection, indicating that neutralizing antibodies detected in an in vitro assay are capable of reducing viral fitness in vivo. In addition, available evidence from acute Infections indicates that high-titer neutralizing antibody responses are present in persons who go on to clear viremia, and not in those who progress to chronicity. We hypothesize that neutralizing antibodies are a predictive marker of clearance of acute HCV infection, and that evasion of these responses is a constrained mechanism for viral persistence. Thus, we propose the following aims to elucidate the clinical utility and basic mechanisms of HCV neutralization: (I) To define the positive predictive value of a potent anti-HCV neutralizing antibody response as a predictor of clearance during acute infection, and (II) To investigate the mechanisms by which HCV evades neutralizing antibody responses during acute infection. Results of studies of cellular immune responses from Project 1 will be integrated to expand knowledge of the interplay between humoral and cellular immune responses to HCV in humans. We have already demonstrated that we can obtain the critical specimens required for this investigation and will be able to conduct unique longitudinal studies of adaptive immune responses in persons transitioning from acute to established infection.