Mechanisms of effective adaptive immunity in HCV treatment

HCV 治疗中有效的适应性免疫机制

• 批准号: 8376379
• 负责人: JOSEPH M MCCUNE
• 金额: $ 34.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376379
• 关键词: Acute; Address; Antigens; Antiviral Agents; Area; CD4 Positive T Lymphocytes; CD8B1 gene; Caring; Case-Control Studies; Cells; Cessation of life; Chronic Hepatitis C; Cirrhosis; Cytotoxic T-Lymphocytes; Data; Dioxygenases; Disabled Persons; Drug Delivery Systems; Frequencies; Goals; Hepatitis C; Hepatitis C virus; Immune; Immune response; Immune system; Immunity; Infection; Interferons; Link; Liver; Malignant neoplasm of liver; Mediating; Morbidity - disease rate; Natural Immunity; Natural Killer Cells; Outcome; Patients; Phenotype; Prospective Studies; Research; Ribavirin; Specimen; T cell response; T-Lymphocyte; United States; Vaccines; Virus; adaptive immunity; base; economic cost; improved; indoleamine; liver biopsy; mortality; neutralizing antibody; peripheral blood; prophylactic; research study; response; social; treatment response

Hepatitis C virus (HCV) infection is the leading cause of liver-related morbidity and mortality in the United States, with an increasing number of deaths due to HCV-associated cirrhosis and liver cancer predicted over the next two decades. Spontaneous clearance is the best outcome of infection, but this occurs in only approximately 15-45% of patients. The goal of this project is to determine the mechanisms of effective adaptive immunity in treatment-mediated clearance of HCV infection. It seems clear that adapfive responses, particulariy CD8* cytotoxic T lymphocyte (CTL) responses, are necessary but not sufficient for HCV clearance. Subjects who respond to antiviral treatment, for example, have a higher frequency of antiviral CTL than do non-responders, but pre-exisfing CTL are insufficient to clear chronic HCV infection. Furthermore, in acute infecfion, effective CTL responses cannot be established in the absence of CD4* T cell help. We speculate that the contributions of CD4* T cells, interferon-a (IFNa), and ribavirin to CDS* T cell responses are linked at the level of the antigen-presenfing cell (APC). We hypothesize that IFNa and ribavirin contribute to HCV clearance in part via an infiuence on the quality of adaptive immune responses that is mediated by effects on APCs and cells of the innate immune system, including NK cells (evaluated in Project 1). In the experiments of this project, this hypothesis will be addressed using specimens of peripheral blood and liver biopsies from pafients in a retrospecfive case-control study and a prospective study of response to standard-of-care treatment of HCV infection. We wish to determine whether a successful response to antiviral treatment for HCV infecfion is related to: (1) enhancement of the polyfuncfionality and maturafion phenotype of CD4'' and CD8* T cells; (2) improved DC function and decreased induction of T regulatory mechanisms (e.g., inducfion of T-regs, indoleamine-2,3-dioxygenase, PD-1, etc); and/ or (3) high titers of total anti-E1/E2 anfibodies or of neutralizing antibodies against HCV. Given the temporal relationship between these parameters and the response to treatment, we may be able to ascertain which are likely to be causal. Viewed in conjunction with the experiments of Project 2 (on innate immunity), we will also be able to better understand the interplay between innate and adaptive immunity in treatment response to HCV.

丙型肝炎病毒（HCV）感染是美国肝脏相关发病率和死亡率的主要原因