Persistent hepatitis C virus replication and T cell immunity in pregnancy

描述(由申请人提供)：慢性丙型肝炎病毒(丙型肝炎病毒)感染的特征是终生稳定的病毒血症，严重进行性肝病的风险显著增加。丙型肝炎病毒持续存在的部分原因是T细胞免疫失败。对成年人的研究表明，细胞毒CD8+T细胞功能耗尽，或针对已突变以逃避识别的病毒表位。CD4+T辅助细胞活性丧失是慢性丙型肝炎的一个标志，但 抑制这一关键免疫反应的机制尚未确定。慢性丙型肝炎病毒感染似乎会因怀孕而改变。病毒血症在怀孕期间增加，然后在分娩后下降，通常是几个对数。我们的中心假设是，对丙型肝炎病毒的细胞免疫在产后完全恢复，至少是短暂的。提出了两个具体目标。具体目的1是比较产后病毒血症显著下降和无病毒血症的妇女的丙型肝炎病毒特异性细胞免疫和潜在的免疫调节变化。具体地说，我们将测试这一假设，即分娩后的病毒控制与CD4+和CD8+T细胞从耗尽状态转变为效应器状态、获得多种效应器功能、对存活细胞因子信号的敏感性以及降低细胞凋亡的易感性有关。此外，我们预计产后病毒血症的下降将与血浆细胞因子和其他促进Th1/Tc1免疫的妊娠相关免疫调节分子的变化有关。具体目的2是确定妊娠和分娩对丙型肝炎病毒基因组和T细胞谱系进化的影响。我们预测，CD8+T细胞免疫在怀孕期间会放松，因此某些I类表位的逃逸突变会恢复到更适合丙型肝炎病毒复制的序列。产后CD8+T细胞免疫的复苏预计会导致I类表位逃逸突变的出现(或重新出现)，并包括新的T细胞克隆型。限制丙型肝炎病毒复制的T细胞免疫的自发恢复将代表着与男性和非怀孕女性所描述的慢性感染的典型模式的重大背离。我们认为，了解丙型肝炎病毒产后自发控制的机制(S)关系到人类健康。例如，它将为在母亲体内病毒复制较低的独特窗口期间治愈感染的策略提供洞察。这些研究还应该提供关于病毒复制适合性和逃逸突变模式之间的关系的信息，这些病毒在怀孕后期出现，可能会传染给半相合的婴儿。更广泛地说，这些研究应该为解开T细胞功能障碍的分子基础以及慢性丙型肝炎和其他慢性病毒感染的免疫调节方法提供一个实质性的新方向。

DESCRIPTION (provided by applicant): Chronic hepatitis C virus (HCV) infection is characterized by stable lifelong viremia and a substantially increased risk of serious progressive liver disease. HCV persists in part because T cell immunity fails. Studies in adults have shown that cytotoxic CD8+ T cells are functionally exhausted or target viral epitopes that have mutated to escape recognition. Loss of CD4+ T helper cell activity is a hallmark of chronic hepatitis C but mechanisms that silence this critical immune response have not been identified. Chronic HCV infection appears to be modified by pregnancy. Viremia increases during pregnancy and then decreases, often by several logs, after childbirth. Our central hypothesis is that cellular immunit to HCV is fully restored, at least transiently, in the postpartum period. Two Specific Aims are proposed. Specific Aim 1 is to compare HCV-specific cellular immunity and underlying immunoregulatory changes in women with and without a substantial drop in viremia in the postpartum period. Specifically we will test the hypothesis that viral control after childbirth is associated with a shift of CD4+ and CD8+ T-cells from an exhausted to an effector state, with acquisition of multiple effector functions, susceptibility to signals from survival cytokines, and decreased predisposition to apoptosis. Further, we anticipate that declining viremia after delivery will be associated with changes in plasma cytokines and other pregnancy-related immunoregulatory molecules that promote Th1/Tc1 immunity. Specific Aim 2 is to determine the influence of pregnancy and delivery on evolution of HCV genomes and T-cell repertoire. We predict that CD8+ T cell immunity is relaxed during pregnancy, so that escape mutations in some class I epitopes revert to a sequence that is more fit for HCV replication. Postpartum resurgence of CD8+ T-cell immunity is expected to cause emergence (or re-emergence) of escape mutations in class I epitopes and include new T-cell clonotypes. Spontaneous recovery of T cell immunity that restricts HCV replication would represent a significant departure from the typical pattern of chronic infection described in men and non-pregnant women. We believe that understanding the mechanism(s) of spontaneous HCV control after childbirth is relevant to human health. For instance, it would provide insight into strategies to cure infection during a unique window of low virus replication in the mothers. The studies should also provide information on the relationship between replicative fitness and patterns of escape mutation in viruses that emerge late in pregnancy and are potentially transmissible to HLA semi-matched infants. More generally, the studies should provide a substantially new direction for unraveling the molecular basis of T cell dysfunction and approaches to immunomodulation in chronic hepatitis C and other chronic viral infections.