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（HCV）感染的特征是稳定的终身病毒血症和严重进行性肝病的风险大幅增加。HCV持续存在的部分原因是T细胞免疫失败。对成人的研究表明，细胞毒性CD 8 + T细胞在功能上已经耗尽，或者靶向已经突变以逃避识别的病毒表位。CD 4 + T辅助细胞活性的丧失是慢性丙型肝炎的标志， 抑制这种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是修改怀孕。病毒血症在怀孕期间增加，然后在分娩后减少，通常减少几个对数。我们的中心假设是，细胞免疫HCV是完全恢复，至少是短暂的，在产后期间。提出了两个具体目标。具体目标1是比较HCV特异性细胞免疫和潜在的免疫调节变化的妇女和没有大幅下降的病毒血症在产后期间。具体来说，我们将测试的假设，即分娩后的病毒控制与转移的CD 4+和CD 8 + T细胞从一个疲惫的效应状态，收购多个效应功能，易感性的信号从生存细胞因子，并减少倾向于凋亡。此外，我们预计，分娩后病毒血症的下降将与血浆细胞因子和其他妊娠相关的免疫调节分子，促进Th 1/Tc 1免疫的变化。具体目标2是确定妊娠和分娩对HCV基因组和T细胞库演变的影响。我们预测，CD 8 + T细胞免疫在怀孕期间是放松的，所以在一些I类表位的逃逸突变恢复到一个更适合HCV复制的序列。产后CD 8 + T细胞免疫的复苏预计会导致I类表位中逃逸突变的出现（或重新出现），并包括新的T细胞克隆型。限制HCV复制的T细胞免疫的自发恢复将代表与在男性和非妊娠女性中描述的慢性感染的典型模式的显著偏离。我们认为，了解分娩后HCV自发控制的机制与人类健康有关。例如，它将提供在母亲体内病毒复制低的独特窗口期治愈感染的策略。这些研究还应提供关于复制适应性与病毒逃逸突变模式之间关系的信息，这些病毒在妊娠后期出现，并可能传播给HLA半匹配的婴儿。更一般地说，这些研究应该为解开T细胞功能障碍的分子基础和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。 公共卫生相关性：该项目与公共卫生有关，因为估计美国1.1%的非监禁妇女感染了HCV。无家可归和被监禁的妇女的死亡率要高出20-40倍。由于许多HCV感染的妇女是育龄妇女，了解病毒复制和免疫在怀孕期间可能有重要意义的发病机制和治疗这种慢性感染。

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. PUBLIC HEALTH RELEVANCE: This project has relevance to public health because an estimated 1.1% of non-incarcerated women in the United States are infected with HCV. The rate is 20-40 times higher in homeless and imprisoned women. Because many HCV-infected women are of childbearing age, an understanding of virus replication and immunity in pregnancy could have important implications for the pathogenesis and therapy of this chronic infection.