Role of HCV in aberrant APC activation/function

HCV 在异常 APC 激活/功能中的作用

• 批准号: 8468021
• 负责人: Young S. Hahn
• 金额: $ 36.86万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468021
• 关键词: Affect; Agonist; Antigen-Presenting Cells; Antiviral Response; Binding; Bypass; CD8B1 gene; Cell Differentiation process; Cell physiology; Cells; Chronic; Chronic Hepatitis; Chronic Hepatitis C; Cirrhosis; Coculture Techniques; Complement 1q; Complement Receptor; Core Protein; Dendritic Cells; Dominant-Negative Mutation; Down-Regulation; Event; Exhibits; Frequencies; Functional disorder; HLA-DR Antigens; Health; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune system; Immunosuppression; Immunosuppressive Agents; Impairment; Individual; Infection; Interferons; Investigation; Lead; Life; Ligands; Liver; MHC Class II Genes; Mediating; Mediator of activation protein; Molecular; Myelogenous; Natural Immunity; Patients; Phenotype; Play; Primary carcinoma of the liver cells; Production; Regulatory T-Lymphocyte; Resistance; Role; STAT3 gene; Suppressor-Effector T-Lymphocytes; T cell response; T-Lymphocyte; Testing; Therapeutic Intervention; Tissue Sample; Up-Regulation; Vaccine Design; Viral; Viremia; Virus Diseases; Work; arginase; base; cytokine; design; hepatitis C virus nucleocapsid protein; improved; inhibitor/antagonist; macrophage; monocyte; novel; novel therapeutics; release factor; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence leading to chronic hepatitis, which in turn predisposes the infected individual to cirrhosis and hepatocellular carcinoma. CD8+ T-cells play a pivotal role in controlling HCV infection; however, severe CD4+ and CD8+ T-cell dysfunction has been observed in chronic HCV patients. This suggests that HCV may employ mechanism(s) to evade or possibly suppress the host T-cell response, although the molecular details have remained elusive. In exploring the possible evasion mechanism(s), we discovered that interaction of HCV-infected hepatocytes with macrophages (M?) and dendritic cells (DCs) of the innate immune system inhibited their ability to produce proinflammatory cytokines. Moreover, the soluble factor(s) released from HCV-infected hepatocytes or the secreted core protein altered APC differentiation and function by the activation of STAT3 transcription factor, which is a crucial event in promoting the induction and expansion of myeloid-derived suppressor cells (MDSCs). Intriguingly, APCs exposed to HCV exhibit the MDSC phenotype with downregulation of HLA-DR and are able to inhibit IFN-?? production by both CD+4+and CD8+ T-cells upon APC-T cell co-culture. Based on these findings, we hypothesize that HCV promotes the induction/expansion of MDSCs via STAT3 activation and that these regulatory APCs in turn suppress T-cell responses. First, we will characterize the role of HCV- induced STAT3 activation in altering APC differentiation and function. Second, we will determine the impact of HCV-mediated APC dysfunction on impairing T cell responses. Lastly, we will explore the mechanism(s) of impairment of T cell responses via HCV-induced APC dysfunction and potential therapeutic intervention. The work proposed in this application will elucidate the mechanism by which HCV evades host innate immunity, resulting in chronic viral infection and its life-threatening complications. We believe that results of these studies will provide a basis fr the rational design of vaccines and novel therapeutics against HCV infection in humans by bypassing the immunosuppressive effect of HCV.

描述（由申请人提供）：人类丙型肝炎病毒（HCV）感染几乎总是与导致慢性肝炎的病毒持续存在相关，而慢性肝炎又使受感染个体易患肝硬化和肝细胞癌。CD 8 + T细胞在控制HCV感染中起关键作用;然而，在慢性HCV患者中观察到严重的CD 4+和CD 8 + T细胞功能障碍。这表明HCV可能采用机制来逃避或可能抑制宿主T细胞应答，尽管分子细节仍然难以捉摸。在探索可能的逃避机制时，我们发现HCV感染的肝细胞与巨噬细胞（M？）先天免疫系统的树突状细胞（DCs）抑制其产生促炎细胞因子的能力。此外，从HCV感染的肝细胞释放的可溶性因子或分泌的核心蛋白通过激活STAT 3转录因子改变APC分化和功能，这是促进髓源性抑制细胞（MDSC）诱导和扩增的关键事件。有趣的是，暴露于HCV的APC表现出MDSC表型，HLA-DR下调，并能够抑制IFN-γ？在APC-T细胞共培养时，CD+4+和CD 8 + T细胞的产生。基于这些发现，我们假设HCV通过STAT 3激活促进MDSC的诱导/扩增，并且这些调节性APC反过来抑制T细胞应答。首先，我们将描述HCV诱导的STAT 3激活在改变APC分化和功能中的作用。其次，我们将确定HCV介导的APC功能障碍对T细胞应答的影响。最后，我们将探讨通过HCV诱导的APC功能障碍和潜在的治疗干预损害T细胞反应的机制。本申请中提出的工作将阐明HCV逃避宿主先天免疫，导致慢性病毒感染及其危及生命的并发症的机制。我们相信，这些研究结果将提供一个基础，为合理设计的疫苗和新的治疗方法，以防止丙型肝炎病毒感染的人类绕过免疫抑制作用。