HIV Pathogenesis: Differential Effects on Lymphocyte Subsets

HIV 发病机制：对淋巴细胞亚群的不同影响

• 批准号: 6431421
• 负责人: DENNIS D. TAUB
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 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/6431421
• 关键词: HIV infections; aging; apoptosis; calcium flux; chemokine; clone cells; cytokine receptors; helper T lymphocyte; host organism interaction; human immunodeficiency virus; human tissue; immunopathology; receptor expression

The human immunodeficiency virus type 1 (HIV-1) is the etiological agent of the acquired immunodeficiency syndrome (AIDS) that develops in HIV-1-infected individuals of all ages after a long clinical latent period. HIV-1-infected elder individuals have a shorter AIDS-free period and shorter life expectancy than individuals aged 13-49 years. With the advent of life-prolonging therapies such as anti-retrovirals and drugs for opportunistic infections, an increase in life expectancy post HIV exposure has been observed worldwide with approximately 580 million HIV-infected subjects over 50 years of age in 1999 compared to approximately 1 billion people expected in 2020. With this increased incidence in aged populations, it is important to determine if AIDS pathology, the HIV infection cycle, and mode of viral transmission are distinct in susceptible cells and/or subjects of differing age groups. Despite the extensive documentation on HIV-1 infectivity, replication within target cells, mechanism(s) of viral immunopathogenesis, and the development of AIDS in adults, no specific cellular- and/or molecular-based studies have been published to date examining any differential infectivity or propagation of HIV-1 within immune cells derived from elderly subjects or within HIV-1-infected elderly patients. Preliminary results from our laboratory have demonstrated significant differences in viral growth between young and aged mononuclear cells. Increased titers of virus were observed in HIV-1-infected aged mononuclear cells and lymphocytes compared to virally-infected cells from younger donors. We believe that aged lymphocytes may be less susceptible to HIV-1-mediated cell death and may serve as a reservoir promoting virion production. We have observed a similar phenomenon using T-helper 1 (Th1) versus T-helper 2 (Th2) populations as well as and Bcl-2 and Bcl-xl-transfected T cells. HIV-1-infected Th1 clones have demonstrated a higher degree of viral susceptibility and death compared to Th2 clones isolated from the same individuals. This differential activity may be partially explained by poor expression of the anti-apoptotic proteins, bcl-2 and bcl-xl, within Th1 clones as well as the differential expression of various HIV co-receptors (chemokine receptors) on their cell surface. Given T cell phenotypic alterations that have been observed in various chronic inflammatory disease states, we believe that a similar systemic phenotype change may occur in circulating T cells of elderly subjects making elder T cells more susceptible to HIV-1 disease. Based on these findings, we are examining various parameters of HIV-1-mediated signaling, replication, apoptosis, and immunopathogenesis using young and aged mononuclear cells, monocytes, and T lymphocytes. In addition, a collaborative clinical trial is being initiated using a cohort of age-, race- and gender-matched control and HIV-infected young and older subjects to assess the in vivo immune and physiological alterations associated with HIV infections in elderly patients. Such information should provide invaluable information on any age-related differences in AIDS pathogenesis.

人类免疫缺陷病毒1型（HIV-1）是获得性免疫缺陷综合征（AIDS）的病原体，其在所有年龄的HIV-1感染个体中经过长的临床潜伏期后发展。 与13-49岁的人相比，感染HIV-1的老年人的无艾滋病期和预期寿命较短。 随着抗逆转录病毒药物和机会性感染药物等延长生命疗法的出现，全球范围内发现艾滋病毒暴露后的预期寿命有所延长，1999年约有5.8亿50岁以上的艾滋病毒感染者，而这一数字预计到2020年将达到约10亿人。随着老年人群中发病率的增加，重要的是要确定艾滋病病理学，HIV感染周期和病毒传播模式在不同年龄组的易感细胞和/或受试者中是否不同。尽管有大量关于HIV-1感染性、靶细胞内复制、病毒免疫发病机制和成人艾滋病发展的文献，但迄今为止尚未发表具体的基于细胞和/或分子的研究，以检查来自老年受试者或HIV-1感染的老年患者的免疫细胞内HIV-1的任何差异感染性或传播。我们实验室的初步结果表明，年轻和老年单核细胞之间的病毒生长存在显着差异。与来自年轻供体的病毒感染细胞相比，在HIV-1感染的老年单核细胞和淋巴细胞中观察到病毒滴度增加。我们认为，老年淋巴细胞可能不太容易受到HIV-1介导的细胞死亡，并可能作为一个水库，促进病毒粒子的生产。 我们使用辅助性T细胞1（Th 1）与辅助性T细胞2（Th 2）群体以及Bcl-2和Bcl-xl转染的T细胞观察到类似的现象。 HIV-1感染的Th 1克隆与分离自相同个体的Th 2克隆相比，表现出更高程度的病毒易感性和死亡。 这种差异活性可以部分地由Th 1克隆内抗凋亡蛋白bcl-2和bcl-xl的表达差以及其细胞表面上各种HIV共受体（趋化因子受体）的差异表达来解释。 鉴于在各种慢性炎症性疾病状态下观察到的T细胞表型改变，我们认为老年受试者的循环T细胞可能发生类似的全身表型变化，使老年T细胞更容易感染HIV-1疾病。基于这些发现，我们正在使用年轻和老年单核细胞、单核细胞和T淋巴细胞研究HIV-1介导的信号传导、复制、凋亡和免疫发病机制的各种参数。 此外，正在启动一项合作临床试验，使用年龄、种族和性别匹配的对照组和艾滋病毒感染的年轻和老年受试者，评估老年患者与艾滋病毒感染相关的体内免疫和生理变化。 这些资料应能提供关于艾滋病发病机制中与年龄有关的任何差异的宝贵信息。