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，其中美国有300万人。 在过去十年中，美国的病毒传播在青少年和年轻人中急剧增加。作为 因此，从2009年到2014年，孕产妇HCV感染的患病率翻了一番。诊断和治疗 这种感染并不常见。关于妊娠对慢性丙型肝炎的影响知之甚少。我们 观察到大约50%的慢性感染妇女在治疗后病毒血症会急剧自发下降， 分娩上一个供资期的观察结果表明，在产后控制持续性 HCV复制。首先，病毒抑制与HLA II类DP和IFN 13基因型相关。第二、 在产后病毒抑制期间，I类HCV表位出现新的逃逸突变是一致的 恢复耗尽的抗病毒CD 8 + T细胞。第三，病毒血症的下降与功能性扩张同时发生， 抗病毒CD 4 + T辅助细胞。这后一观察结果是重要的，因为慢性丙型肝炎以外的 妊娠以稳定的病毒血症和循环功能性HCV特异性CD 4 + T细胞的缺乏为标志。 该更新申请的中心假设是，CD 4 + T细胞帮助的恢复导致免疫功能的恢复。 CD 8 + T细胞和B细胞应答抑制分娩后HCV复制 提出了两个具体目标。目的1将比较CD 4+（子目的1a）和CD 8+（子目的1b）T细胞应答 在怀孕期间和之后。我们预测，恢复的CD 4 + T细胞具有表型，转录， 和功能谱与T辅助细胞（Th）和T滤泡辅助细胞（Tfh）亚群一致， 分别产生抗病毒的CD 8 + T细胞和B细胞。在目标1b中，我们预测病毒抑制是 与靶向完整I类HCV表位的功能性CD 8 + T细胞的扩增相关。cd 8 + T细胞 在慢性丙型肝炎中，靶向完整表位是最彻底耗尽和难以挽救的。目的2 是为了描述妊娠期独特环境中HCV B细胞反应的特征。它将利用创新的 四聚体组成的HCV E2包膜糖蛋白可视化和丰富抗病毒B细胞期间和之后 怀孕这种独特的试剂将有助于分析B细胞是否经历频率变化， 表型、转录谱和/或与功能恢复和病毒控制一致的库。在 平行研究表明，分娩后抗体反应是否会扩大以中和同期病毒， 接受检查。总之，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，并深入了解与开发所需预防性药物相关的效应机制。 HCV疫苗。更一般地说，我们希望填补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.