INHIBITION OF HIV-1 REPLICATION BY CYTOTOXIC LYMPHOCYTES

细胞毒性淋巴细胞抑制 HIV-1 复制

• 批准号: 3145914
• 负责人: Bruce D Walker
• 金额: $ 23.89万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3145914
• 关键词: AIDS; CD8 molecule; HIV infections; RNA directed DNA polymerase; T lymphocyte; cell mediated lymphocytolysis test; chromium; clone cells; cytokine; cytotoxic T lymphocyte; genetic manipulation; host organism interaction; human immunodeficiency virus 1; human subject; macrophage; molecular cloning; monoclonal antibody; monocyte; polymerase chain reaction; radionuclides; radiotracer; tissue /cell culture; virus antigen; virus replication

Despite the identification of HIV-1 as the causative agent of the acquired immune deficiency syndrome (AIDS), definition of a protective immune response against the virus has remained an elusive goal. A vigorous cytotoxic lymphocyte (CTL) response to HIV-1 has been detected in infected individuals, and in vitro data indicate that lymphocytes from infected individuals of the CD8 phenotype can inhibit virus replication in vitro. Functional studies suggest that these cells are typical CTL, yet the relevant target antigens recognized have not been identified. Our laboratory has recently established a technique for the isolation and long-term propogation of HIV-1-specific CTL clones, and have mapped the actual CTL epitopes recognized by these cells using synthetic viral peptides. The purpose of this proposal is to examine the ability of CTL clones of defined epitope specificity to inhibit the replication of HIV-1 in order to determine the functional activity of these cells in vitro. Specifically, we propose to (1) examaine the ability of CTL clones to inhibit replication of HIV-1 in lymphocytes (2) examine the ability of CTL clones to inhibit HIV-1 replication in monocytes (3) determine the mechanisms of the CTL-induced inhibition of virus replication (4) determine the role of antigenic variation in escape from CTL recognition. These studies should both provide insight into the immunopathogenesis of HIV-1 infection, and are directly relevant to potential HIV-1 immunization and immunotherapy strategies.

尽管艾滋病毒-1被确认为 获得性免疫缺陷综合征(艾滋病)，保护性的定义 对病毒的免疫反应仍然是一个难以实现的目标。一个 检测到对HIV-1有强烈的细胞毒性淋巴细胞(CTL)反应 在感染的个体中，体外数据表明淋巴细胞 来自感染CD8表型的个体可以抑制病毒 体外复制。功能研究表明，这些细胞是 典型的CTL，但相关的靶抗原尚未被识别 确认身份。我们实验室最近建立了一种技术，用于治疗 HIV-1特异性CTL克隆的分离和长期繁殖，以及 已经绘制了这些细胞识别的实际CTL表位图 人工合成的病毒多肽。这项建议的目的是审查 具有特定表位特异性的CTL克隆抑制AFP的能力 复制HIV-1以确定其功能活性 这些细胞在体外。具体地说，我们建议(1)审查 CTL克隆抑制HIV-1在淋巴细胞中复制的能力(2) 检测CTL克隆抑制HIV-1复制的能力 单核细胞(3)确定CTL抑制细胞增殖的机制 病毒复制(4)决定抗原变异在疾病中的作用 逃避CTL识别。这两项研究都应该提供洞察力 HIV-1感染的免疫致病机制，并直接 与潜在的艾滋病毒-1免疫和免疫治疗战略相关。