Humoral Immune Response to Acute HCV Infection

项目2的主要目标是通过检测有效的中和抗体反应的临床和分子相关性来扩展我们对急性丙型肝炎病毒(HCV)感染的体液免疫反应的研究。我们最近证明，在急性感染期间，抗丙型肝炎病毒中和抗体驱动丙型肝炎病毒蛋白E1和E2的进化，表明在体外检测到的中和抗体能够降低体内病毒的适合性。此外，来自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，而不存在于进展为慢性病的人中。我们假设中和抗体是清除红斑狼疮的预测标记物 急性丙型肝炎病毒感染，而逃避这些反应是病毒持续存在的一种受限机制。因此，我们提出以下目的来阐明丙型肝炎病毒中和试验的临床应用和基本机制：(I)确定有效的抗丙型肝炎病毒中和抗体应答的阳性预测价值，作为急性感染期间清除的预测因子；(Ii)研究丙型肝炎病毒在急性感染期间逃避中和抗体应答的机制。项目1对细胞免疫反应的研究结果将被整合，以扩大对人类对丙型肝炎病毒的体液和细胞免疫反应之间相互作用的知识。我们已经证明，我们可以获得这项研究所需的关键样本，并将能够对从急性感染过渡到已确诊感染的人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.