Persistent hepatitis C virus replication and T cell immunity in pregnancy

妊娠期丙型肝炎病毒持续复制和 T 细胞免疫

• 批准号: 8416956
• 负责人: Christopher M. Walker
• 金额: $ 54.95万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416956
• 关键词: Adult; Apoptosis; Apoptotic; Avidity; CD4 Positive T Lymphocytes; CD8B1 gene; Cellular Immunity; Childbirth; Chronic; Chronic Hepatitis C; Cytotoxic T-Lymphocytes; Data; Drops; Environment; Epitopes; Evolution; Female of child bearing age; Figs - dietary; Frequencies; Functional disorder; Generations; Genes; Genome; Health; Helper-Inducer T-Lymphocyte; Hepatitis C; Hepatitis C virus; Homelessness; Human; Immune; Immune response; Immunity; Individual; Infant; Infection; Left; Liver diseases; Molecular; Mothers; Mutate; Mutation; Natural Immunity; Pathogenesis; Pattern; Plasma; Postpartum Period; Predisposition; Pregnancy; Public Health; Recovery; Resolution; Risk; Serum; Signal Transduction; T cell response; T-Lymphocyte; Testing; Time; United States; Ursidae Family; Vaccines; Variant; Viral; Viremia; Virus; Virus Diseases; Virus Replication; Woman; Work; base; cost; cross reactivity; cytokine; cytotoxic; exhaust; exhaustion; experience; falls; fitness; immunoregulation; insight; men; pressure; receptor; reconstitution

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.

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脏疾病的风险大大增加。 HCV持续存在部分是因为T细胞免疫失败。成年人的研究表明，细胞毒性CD8+ T细胞在功能上耗尽或靶向病毒表位，已突变以逃避识别。 CD4+ T辅助细胞活性的丧失是慢性丙型肝炎的标志，但 尚未确定这种关键免疫反应的沉默的机制。慢性HCV感染似乎通过妊娠改变了。病毒血症在怀孕期间增加，然后在分娩后通常通过几个原木减少。我们的中心假设是，至少在产后时期，对HCV的细胞免疫是完全恢复的。提出了两个具体目标。具体目的1是比较HCV特异性的细胞免疫和在产后病毒血症有大幅下降的女性中的免疫调节性变化。具体而言，我们将测试以下假设：分娩后的病毒控制与CD4+和CD8+ T细胞从耗尽的效应状态转移，并获得了多种效应子功能，对来自生存细胞因子的信号的敏感性以及对凋亡的倾向降低。此外，我们预计输送后的病毒血症下降将与血浆细胞因子的变化和其他促进TH1/TC1免疫的免疫调节分子的变化有关。具体目的2是确定妊娠和递送对HCV基因组进化和T细胞库的影响。我们预测CD8+ T细胞的免疫力在怀孕期间放松，因此某些I类表位的逃生突变还原为更适合HCV复制的序列。 CD8+ T细胞免疫的产后复活有望在I类表位中引起逃生突变的出现（或重新出现），并包括新的T细胞clonotypes。限制HCV复制的T细胞免疫的自发恢复将与男性和未怀孕妇女描述的典型慢性感染模式有很大的不同。我们认为，了解分娩后自发性HCV控制的机制与人类健康有关。例如，它将提供有关母亲病毒复制低的独特窗口中治愈感染的策略的见解。这些研究还应提供有关在怀孕后期出现的病毒中复制适应性与逃生突变模式之间关系的信息，并且可能对HLA半匹配的婴儿可以传播。更普遍地，研究应为揭示T细胞功能障碍的分子基础和在慢性丙型肝炎和其他慢性病毒感染中的免疫调节方法提供基本的新方向。