PATHOGENIC MECHANISMS IN HIV AND OTHER RETROVIRAL INFECTIONS

HIV 和其他逆转录病毒感染的致病机制

• 批准号: 2566816
• 负责人: H C LANE
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2566816
• 关键词: AIDS; AIDS therapy; CD4 molecule; CD8 molecule; HIV infections; SCID mouse; T cell receptor; T lymphocyte; antiAIDS agent; antigen receptors; antiviral agents; clinical research; drug screening /evaluation; human immunodeficiency virus 1; human subject; molecular pathology; nonhuman therapy evaluation; nucleoside analog; polymerase chain reaction; tissue /cell culture

An intensive effort was directed toward attempting to better understand the immunopathologic mechanisms underlying the immunodeficiency of HIV-1 infection. To determine whether or not alterations in the fine specificity of the CD4+ T lymphocyte repertoire could underly the defect, a polymerase chain reaction (PCR) based technique was used to determine the relative levels of mRNAs encoding the T cell antigen receptor beta- chain for each of the 24 human variable domain beta-chain subfamilies. Disruptions of the normal size pattern were noted in the majority of patients with HIV infection, particularly those patients with low CD4+ T lymphocyte counts. While protease or IL-2 therapy could result in substantial increases in CD4+ T lymphocyte numbers, they led to little if any changes in the distribution of size patterns. The HIV-hu/PBL-SCID model was employed to study the immune systems of long-term non-progressors and to evaluate the potential anti-viral activity of novel therapeutic interventions. Mice reconstituted with PBMC from long-term non-progressors failed to show evidence of CD4+ T lymphocyte depletion. The nucleoside analogue FddA was found to be a potent anti-retroviral compound. CD8+ T lymphocytes from patients with HIV infection were found to have increased expression of the activiation markers HLA-DR, CD57, CD45RO and Fas. These cells were unable to be stimulated by standard signals. Analysis of these cells revealed increased levels of cdk2 and cyclin E as well as persistence of p27kip, suggesting that they were blocked at the G1/S checkpoint of the cell cycle. A similar phenotype could be generated in vitro by stimulation of CD8+ T lymphocytes from healthy donors with PHA only in the absence of IL-2 suggesting that this in vivo observation may stem from in vivo activation of CD8+ T lymphocytes in the absence of the second signals provided by CD4+ T lymphocytes. Analysis of the T cell receptor repertoire in the CD8+ T lymphocytes of patients with HIV infection revealed that while the DR- subpopulation represented a polyclonal population, the DR+ subpopulation of cells was oligoclonal.

强烈的努力是为了更好地理解 HIV-1免疫缺陷的背后的免疫病理机制 感染。 确定罚款中是否发生变化 CD4+ T淋巴细胞库的特异性可能是在缺陷的基础 聚合酶链反应（PCR）技术用于确定 编码T细胞抗原受体β-的mRNA的相对水平 24个人类可变结构域β链亚家族中的链。 大多数人都注意到正常大小模式的破坏 HIV感染的患者，特别是CD4+低的患者 T淋巴细胞计数。 虽然蛋白酶或IL-2疗法可能会导致 CD4+ T淋巴细胞的大幅增加，它们导致很少 如果大小模式的分布有任何变化。 HIV-HU/PBL-SCID 模型被用于研究长期的免疫系统 非培训器并评估 新颖的治疗干预措施。 与PBMC重构的小鼠 长期非培训器未能显示CD4+ T淋巴细胞的证据 消耗。 发现核苷类似物FDDA是有效的 抗逆转录病毒化合物。来自HIV患者的CD8+ T淋巴细胞 发现感染的激活表达增加 标记HLA-DR，CD57，CD45RO和FAS。 这些细胞无法 由标准信号刺激。 对这些细胞的分析显示 CDK2和细胞周期蛋白E的水平增加以及P27KIP的持久性， 表明它们在单元的G1/s检查点上被阻塞 循环。 可以通过刺激在体外产生类似的表型 仅在没有PHA的健康供体的CD8+ T淋巴细胞的 IL-2表明这种体内观察可能源于体内 在没有第二个信号的情况下，CD8+ T淋巴细胞的激活 由CD4+ T淋巴细胞提供。 T细胞受体的分析 HIV感染患者的CD8+ T淋巴细胞中的曲目 揭示了DR-Subpropulation代表多克隆 细胞的DR+亚群的种群是寡聚的。