Persistent hepatitis C virus replication and immunity in pregnancy

妊娠期丙型肝炎病毒的持续复制和免疫力

• 批准号: 10413150
• 负责人: Christopher M. Walker
• 金额: $ 60.92万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413150
• 关键词: Acute; Acute Hepatitis C; Adolescent and Young Adult; Adoption; Antibodies; Antibody Response; Appearance; B-Lymphocytes; Birth; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Childbirth; Chronic; Chronic Hepatitis C; Development; Diagnosis; Drops; Epitopes; Evolution; Failure; Female of child bearing age; Frequencies; Funding; Gene Expression Profile; Genes; Genetic Transcription; Genotype; Glycoproteins; Helper-Inducer T-Lymphocyte; Hepatitis B Virus; Hepatitis C; Hepatitis C Transmission; Hepatitis C Vaccine; Hepatitis C virus; Hepatocyte; Human; Immune; Immune Response Genes; Immune response; Immunity; Immunoglobulin Genes; Impairment; Individual; Infection; Interferon Type II; Interleukin-2; Knowledge; Link; Liver; Liver diseases; Malignant neoplasm of liver; Mediating; Monitor; Mutation; Natural regeneration; Persons; Phase; Phenotype; Population; Postpartum Period; Pregnancy; Prevalence; Preventive; Reagent; Recovery; Recovery of Function; Regimen; Reporting; Research; Resolution; Risk; Serum; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; United States; Vaccines; Viremia; Virus; Virus Diseases; Virus Replication; Visualization; Woman; adaptive immune response; antiviral drug development; antiviral immunity; chronic infection; cytokine; design; effector T cell; exhaust; exhaustion; experience; innovation; insight; neutralizing antibody; pressure; prevent; receptor; response; restoration; viral transmission

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.

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。 过去十年，美国青少年和年轻人中的病毒传播急剧增加。作为 因此，从 2009 年到 2014 年，孕产妇 HCV 感染率翻了一番。 诊断和治疗 这些感染并不常见。关于怀孕对慢性丙型肝炎的影响知之甚少。我们 据观察，大约 50% 的慢性感染女性在感染后病毒血症会急剧、自发下降。 分娩。上一个资助期的观察表明，这种产后控制持续存在的免疫力 丙肝病毒复制。首先，病毒抑制与HLA II类DP和IFN13基因型相关。第二， 在产后病毒抑制过程中，I 类 HCV 表位中新逃逸突变的出现是一致的 随着耗尽的抗病毒 CD8+ T 细胞的恢复。第三，病毒血症下降与功能性扩张同时发生。 抗病毒 CD4+ T 辅助细胞。后一个观察结果很重要，因为慢性丙型肝炎在 妊娠的特点是稳定的病毒血症和循环功能性 HCV 特异性 CD4+ T 细胞的缺失。 该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 细胞反应可抑制分娩后 HCV 复制。 提出了两个具体目标。目标 1 将比较 CD4+ (subaim 1a) 和 CD8+ (subaim 1b) T 细胞反应 女性怀孕期间和怀孕后。我们预测恢复的 CD4+ T 细胞具有表型、转录、 和功能特征与 T 辅助细胞 (Th) 和 T 滤泡辅助细胞 (Tfh) 亚群一致，对于 分别开发抗病毒 CD8+ 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 CD8+ T 细胞的扩增相关。 CD8+ T细胞 针对慢性丙型肝炎，靶向完整表位是最彻底且难以挽救的。目标 2 旨在表征妊娠独特环境中 HCV B 细胞的反应。它将利用创新的 由 HCV E2 包膜糖蛋白组成的四聚体，可在治疗期间和治疗后可视化并富集抗病毒 B 细胞 怀孕。这种独特的试剂将有助于分析 B 细胞是否发生频率变化， 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，分娩后抗体反应是否会扩大以中和同期病毒 被检查。总之，这些研究有望提供 T 细胞和 B 细胞恢复的详细概况 在慢性感染期间，深入了解与开发所需预防措施相关的效应机制 丙肝疫苗。更一般地说，我们期望填补有关持久性病毒的知识的重要空白 怀孕期间的感染和免疫力。

项目成果

Defer no more: advances in the treatment and prevention of chronic hepatitis C virus infection in children.

• DOI: 10.1097/qco.0000000000000856
• 发表时间: 2022-10-01
• 期刊: Current opinion in infectious diseases
• 影响因子: 3.9

New prospects for the treatment and prevention of hepatitis C in children.

• DOI: 10.1097/mop.0000000000000313
• 发表时间: 2016-02
• 期刊: Current opinion in pediatrics
• 影响因子: 3.6
• 作者: Ohmer S;Honegger J
• 通讯作者: Honegger J