The effects of hepatitis C virus (HCV) E2 protein on host immunomodulation

丙型肝炎病毒（HCV）E2蛋白对宿主免疫调节的影响

• 批准号: 8540646
• 负责人: Jack T. Stapleton
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8540646
• 关键词: Address; Adverse effects; Antiviral Agents; Antiviral Therapy; Autoimmune Diseases; CD8B1 gene; Caring; Cells; Chronic; Cirrhosis; Cryoglobulinemia; Data; Development; Disease; Flaviviridae; Flavivirus; GB virus C; Glycoproteins; HCV Liver Disease; Hepatic; Hepatitis C; Hepatitis C virus; Human; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; In Vitro; Individual; Infection; Inflammation; Lead; Liver; Liver diseases; Lymphocyte; Lymphocyte-Specific p56LCK Tyrosine Protein Kinase; Mediating; Medical; Microbe; Mus; Non-Hodgkin' s Lymphoma; Pathogenesis; Pathogenicity; Phosphorylation; Plasma; Population; Prevention; Primary carcinoma of the liver cells; Process; Proteins; Proteome; Publishing; Regulation; Signal Transduction; System; T cell response; T-Cell Receptor; T-Lymphocyte; Vaccines; Veterans; Viral; Viral Proteins; Virion; Virus; Work; base; chronic liver disease; immunoregulation; improved; in vivo; member; novel; novel strategies; novel therapeutics; pathogen; public health relevance; therapeutic target; vaccine development; viral RNA; virus envelope

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is an important and worldwide cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. HCV is over-represented among veterans, and the VA medical system provides care for the largest population of HCV-infected people in the U.S. Host immune recognition of HCV develops slowly following infection, and CD4+ and CD8+ T cell responses develop weeks to months after infection if they develop at all. After viral persistence is established, HCV-specific CD4+ and CD8+ T cells are readily detected in most infected individuals, yet these T cells are ineffective in controlling viral replication. Although several vral proteins have been shown to interfere with various aspects of the host innate and adaptive immune response, a clear mechanism by which HCV diminishes CD4+ and CD8+ T cell immune responses is lacking. In addition to liver disease, HCV also is responsible for a variety of non- hepatic complications. The pathogenesis of non-hepatic HCV-related diseases may reflect abnormal regulation of host immune responses (e.g. cryoglobulinemia), chronic inflammation and/or decreased immune surveillance (e.g. non-Hodgkins lymphoma [NHL]). Fortunately, antiviral therapy for HCV infection has dramatically improved in the past few years, and the use of combination direct antiviral agents has a great potential for virological cure. However, because HCV treatment may have serious side effects, is expensive, and is not completely effective, it is important to better understand host immune responses to this pathogen for identifying alternative therapeutic targets and to facilitate vaccine development. We provide preliminary data demonstrating that the HCV E2 envelope glycoprotein competitively inhibits T cell signaling through the T cell receptor. Based on work in the most closely related human flavivirus (GB virus C; GBV-C), we hypothesize that E2 protein competes with the key proximal lymphocyte-specific protein tyrosine kinase (Lck) by serving as an alternative substrate for phosphorylation. As a consequence of this interaction, signaling is reduced following T cell receptor engagement, contributing to persistent HCV infection, a decrease in host immune surveillance mechanisms, and resultant increase in the development of altered host immune responses. We further hypothesize that HCV E2 protein and HCV virions modulate immune responses in uninfected bystander cells including lymphocytes. Published work is consistent with HCV infection altering TCR-mediated signaling in vivo, and that HCV proteins blunt proliferation following TCR stimulation in vitro in humans in and mice. Our preliminary work suggests that this may be mediated at least in part by HCV E2 protein, and that the effect on bystander cells involves the transfer of E2 in exosomes to surrounding cells. In this proposal we will characterize the HCV envelope glycoprotein E2 effects on TCR signaling, and confirm the mechanism of the effects on bystander T cells. In addition, we will characterize the constituents of HCV envelope glycoprotein E2 containing exosomes, and in exosomes present in the plasma of HCV-infected subjects. These studies will characterize a novel mechanism of HCV-mediated immunomodulation that is likely to contribute to persistence and may influence non-hepatic HCV- related disease processes. Identification and characterization of this HCV E2 - lymphocyte interaction may contribute to the development of novel therapeutic and/or vaccine approaches to HCV, and potentially to related viruses within the Flaviviridae.

描述（由申请人提供）： 丙型肝炎病毒（HCV）是慢性肝病、肝硬化和肝细胞癌的重要和全球性原因。HCV在退伍军人中的代表性过高，VA医疗系统为美国最大的HCV感染人群提供护理。HCV的宿主免疫识别在感染后缓慢发展，CD 4+和CD 8 + T细胞反应在感染后数周至数月发展。在病毒持续存在后，HCV特异性CD 4+和CD 8 + T细胞在大多数感染个体中很容易检测到，但这些T细胞在控制病毒复制方面无效。尽管已经显示几种病毒蛋白质干扰宿主先天性和适应性免疫应答的各个方面，但缺乏HCV减少CD 4+和CD 8 + T细胞免疫应答的明确机制。除了肝脏疾病外，HCV还引起多种非肝脏并发症.非肝脏HCV相关疾病的发病机制可能反映宿主免疫应答的异常调节（例如，冷球蛋白血症）、慢性炎症和/或免疫监视降低（例如，非霍奇金淋巴瘤[NHL]）。幸运的是，在过去的几年里，HCV感染的抗病毒治疗已经有了很大的改善，并且联合使用直接抗病毒药物具有很大的病毒学治愈潜力。然而，由于HCV治疗可能有严重的副作用，是昂贵的，并不完全有效，重要的是要更好地了解宿主对这种病原体的免疫反应，以确定替代治疗靶点，并促进疫苗的开发。我们提供的初步数据表明，HCV E2包膜糖蛋白竞争性抑制T细胞信号通过T细胞受体。基于最密切相关的人类黄病毒（GB病毒C; GBV-C）的工作，我们假设E2蛋白与关键的近端淋巴细胞特异性蛋白酪氨酸激酶（LCK）竞争，作为磷酸化的替代底物。作为这种相互作用的结果，信号传导在T细胞受体接合后减少，导致持续的HCV感染，宿主免疫监视机制减少，并导致宿主免疫应答改变的发展增加。我们进一步假设，HCV E2蛋白和HCV病毒粒子调节未感染的旁观者细胞，包括淋巴细胞的免疫反应。已发表的工作与HCV感染在体内改变TCR介导的信号传导一致，并且HCV蛋白在人和小鼠中在体外抑制TCR刺激后的增殖。我们的初步工作表明，这可能是介导的至少部分由HCV E2蛋白，并对旁观者细胞的影响涉及E2的外泌体转移到周围的细胞。在本研究中，我们将描述HCV包膜糖蛋白E2对TCR信号传导的影响，并证实其对旁观者T细胞的作用机制。此外，我们将表征含有外泌体的HCV包膜糖蛋白E2的成分，以及HCV感染受试者血浆中存在的外泌体。这些研究将描述HCV介导的免疫调节的一种新机制，这种机制可能有助于持续存在，并可能影响非肝脏HCV相关疾病的过程。这种HCV E2 -淋巴细胞相互作用的鉴定和表征可能有助于开发针对HCV的新型治疗和/或疫苗方法，并可能有助于黄病毒科内的相关病毒。