CD4+T CELL EXPANSIONS IN HIV

HIV 中的 CD4 T 细胞扩增

• 批准号: 2887951
• 负责人: Brian L Kotzin
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887951
• 关键词: HIV infections; T cell receptor; clinical research; helper T lymphocyte; human subject; hybridomas; immunopathology; lymphocyte proliferation; molecular cloning; receptor expression; virus DNA; virus antigen

This application proposes to use PBMC specimens collected from two ACTG protocols to retrospectively study clonal expansions in the CD4 lymphocyte repertoire that occur in HIV infection and their response(s) to HAART. The PI has recently identified large clonal/oligoclonal expansions in CD4 cells in a limited number of patients with HIV. Previous work by the PI has shown that clonal expansions of CD4 cells in the periphery are not found in a large sampling of 147 healthy children and adults, from a broad range of ages, or in autoimmune disease states, such as rheumatoid arthritis. Therefore, such clonal CD4 cell expansions may be unique to HIV infection. It is hypothesized that the expanded CD4 cell clones arise from proliferation to specific HIV antigens, but they have been rendered functionally deficient by the disease process. The goal of this proposal is to determine the clonal or oligoclonal nature of CD4 cell subsets that express particular TCR V-beta determinants in HIV patients, prior to therapy and following up to 80 weeks of HAART. Subsets representing both expanded and non- expanded V-beta phenotypes will be analyzed to: 1) compare their proliferative capacity in vitro, 2) determine changes in TCR diversity following HAART, and 3) derive TCR sequences to be expressed in a transgenic hybridoma cell model to screen for specific reactivity to HIV antigen epitopes. In addition, experiments will be done to determine whether expanded subsets of CD4 cells harbor increased HIV DNA load in comparison to non-expanded subsets, and whether any differential levels in viral DNA persist following extended HAART.

本申请建议使用从两个 ACTG 采集的 PBMC 样本 回顾性研究 CD4 克隆扩增的方案 HIV 感染中出现的淋巴细胞库及其反应 进行HAART治疗。 PI 最近发现了大克隆/寡克隆 有限数量的 HIV 患者体内 CD4 细胞的扩增。 PI 之前的工作表明 CD4 细胞的克隆扩增 在 147 名健康人的大样本中未发现 儿童和成人，各个年龄段，或患有自身免疫性疾病 疾病状态，例如类风湿性关节炎。 因此，这样的克隆 CD4 细胞扩增可能是 HIV 感染所特有的。 据推测 扩增的 CD4 细胞克隆是从增殖到特定的 HIV抗原，但它们已被赋予功能缺陷 疾病过程。 该提案的目标是确定克隆 或表达特定 TCR 的 CD4 细胞亚群的寡克隆性质 HIV 患者治疗前和随访中的 V-β 决定因素 至 80 周的 HAART。 代表扩展和非扩展的子集 将分析扩展的 V-beta 表型以：1) 比较它们的 体外增殖能力，2) 确定 TCR 多样性的变化 遵循HAART，并且3)导出TCR序列以表达 用于筛选对 HIV 特异性反应的转基因杂交瘤细胞模型 抗原表位。 此外，还将进行实验以确定 扩大的 CD4 细胞亚群是否会增加 HIV DNA 载量 与非扩展子集的比较，以及是否有任何差异水平 延长HAART后，病毒DNA中的病毒仍然存在。