Persistent hepatitis C virus replication and immunity in pregnancy

据估计，全球有7100万人患有慢性丙型肝炎，其中包括美国的300万人。 在过去的十年里，病毒在美国青少年和年轻人中的传播急剧增加。AS 因此，从2009年到2014年，产妇感染丙型肝炎病毒的流行率翻了一番。诊断和治疗 这些感染中的一种并不常见。关于怀孕对慢性丙型肝炎的影响，我们知之甚少。 观察到，大约50%的慢性感染妇女经历了病毒血症的急剧、自发的下降 分娩。上一次资助期的观察表明，在产后持续性控制中存在免疫力 丙型肝炎病毒复制。首先，病毒抑制与人类白细胞抗原II类DP和IFNL3基因相关。第二, 产后病毒抑制期间I型丙型肝炎病毒表位出现新的逃逸突变是一致的 随着耗尽的抗病毒CD8+T细胞的恢复。第三，病毒血症的下降与功能的扩大是一致的。 抗病毒的CD4+T辅助细胞。后一种观察结果意义重大，因为慢性丙型肝炎 妊娠的特点是稳定的病毒血症，循环中缺乏功能正常的丙型肝炎病毒特异性CD4+T细胞。 这种更新应用的中心假设是，CD4+T细胞的恢复有助于恢复 CD8+T细胞和B细胞在分娩后抑制丙型肝炎病毒复制。 提出了两个具体目标。目标1将比较CD4+(亚目的1a)和CD8+(亚目的1b)T细胞的反应 在怀孕期间和怀孕后的妇女中。我们预测，恢复的CD4+T细胞具有表型、转录和 以及与T辅助细胞(Th)和T滤泡辅助细胞(Tfh)亚群一致的功能特征 抗病毒CD8+T细胞和B细胞的发育。在目标1b中，我们预测病毒抑制是 与针对完整的丙型肝炎病毒I类表位的功能性CD8+T细胞的扩增有关。CD8+T细胞 靶向完整的表位是慢性丙型肝炎最彻底耗尽和最难挽救的。 是描述在妊娠的特殊环境下丙型肝炎病毒B细胞的反应。它将利用创新的 由丙型肝炎病毒包膜糖蛋白组成的四聚体在体内和术后显影和浓缩抗病毒B细胞 怀孕了。这种独特的试剂将有助于分析B细胞是否经历频率变化， 与功能恢复和病毒控制一致的表型、转录特征和/或谱系。在……里面 平行研究表明，分娩后抗体反应是否会扩大以中和同时期的病毒 接受检查。总而言之，这些研究有望提供T和B细胞恢复的详细情况 在慢性感染期间，并洞察与开发所需预防措施相关的效应机制 丙型肝炎疫苗。更广泛地说，我们希望填补关于持久性病毒的知识的一个重要空白 怀孕期间的感染和免疫力。

Globally it is estimated that 71 million people have chronic hepatitis C, including 3 million in the United States. Virus transmission in the US increased sharply over the last decade amongst adolescents and young adults. As a consequence, the prevalence of maternal HCV infection doubled from 2009 to 2014. Diagnosis and treatment of these infections is uncommon. Little is known about the influence of pregnancy on chronic hepatitis C. We observed that about 50% of chronically infected women experience a sharp, spontaneous drop in viremia after childbirth. Observations from the last funding period implicate immunity in this post-partum control of persistent HCV replication. First, virus suppression was associated with HLA class II DP and IFNl3 genotype. Second, appearance of new escape mutations in class I HCV epitopes during postpartum virus suppression is consistent with recovery of exhausted antiviral CD8+ T cells. Third, declining viremia coincided with expansion of functional antiviral CD4+ T helper cells. This latter observation is significant because chronic hepatitis C outside of pregnancy is marked by stable viremia and an absence of circulating functional HCV-specific CD4+ T cells. The central hypothesis of this renewal application is that recovery of CD4+ T cell help results in restoration of CD8+ T cell and B cell responses that suppress HCV replication after childbirth. Two specific aims are proposed. Aim 1 will compare CD4+ (subaim 1a) and CD8+ (subaim 1b) T cell responses in women during and after pregnancy. We predict that recovered CD4+ T cells have phenotypic, transcriptional, and functional profiles consistent with T helper (Th) and T follicular helper (Tfh) sub-populations important for development of antiviral CD8+ T cells and B cells, respectively. In Aim 1b, we predict that virus suppression is associated with expansion of functional CD8+ T cells targeting intact class I HCV epitopes. CD8+ T cells targeting intact epitopes are the most thoroughly exhausted and difficult to rescue in chronic hepatitis C. Aim 2 is to characterize HCV B cell responses in the unique setting of pregnancy. It will take advantage of an innovative tetramer comprised of the HCV E2 envelope glycoprotein to visualize and enrich antiviral B cells during and after pregnancy. This unique reagent will facilitate an analysis of whether B cells undergo changes in frequency, phenotype, transcriptional profile, and/or repertoire consistent with functional recovery and virus control. In parallel studies, whether antibody responses broaden after childbirth to neutralize contemporaneous viruses will be examined. In summary, these studies are expected to provide a detailed profile of T and B cell recovery during chronic infection, and insight into effector mechanisms relevant to development of a needed preventive HCV vaccine. More generally, we expect to fill an important gap in knowledge regarding persistent virus infections and immunity during pregnancy.