HIV Pathogenesis: Differential Effects on Lymphocyte Sub

HIV 发病机制：对淋巴细胞亚群的不同影响

• 批准号: 7324968
• 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/7324968
• 关键词: HIV; Pathogenesis; Differential; Effects; Lymphocyte

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-retroviral 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. Results from our laboratory have demonstrated significant differences in viral growth between young and aged human and primate 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. Given T cell phenotypic alterations that have been observed in various chronic inflammatory disease states and aging, we believe that a similar systemic Th2 polarization may occur in circulating T cells of elderly subjects making them more susceptible to HIV-1 disease. Based on these findings, we are examining various parameters of HIV-1-mediated signaling, replication and immunopathogenesis using young and aged mononuclear cells and T lymphocytes. Additional studies are being performed examining alterations in the circulating homocysteine, vitamin B12, folate, and red blood cell folate levels in these subjects to determine if there are any age- and HIV-related changes in these subjects and any possible correlations with immune phenotypes and cellular apoptosis. Such information should provide invaluable information on any age-related differences in AIDS pathogenesis. Finally, we have identified several new and novel chemokine receptor antagonists that block several receptors and are capable of blocking HIV infectivity and binding as well as chemokine function. We believe these antagonists may have potential therapeutic value in the treatment of AIDS.

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，所有年龄段的HIV-1感染者在经历了较长的临床潜伏期后都会发生艾滋病。与13-49岁的人相比，感染艾滋病毒-1的老年人的无艾滋病期和预期寿命更短。随着治疗机会性感染的抗逆转录病毒药物等延长生命的疗法的出现，世界各地暴露于艾滋病毒后的预期寿命有所增加，1999年50岁以上的艾滋病毒感染者约为5.8亿，而2020年预计约为10亿人。随着老年人群发病率的增加，重要的是确定艾滋病的病理、艾滋病毒感染周期和病毒传播方式在不同年龄组的易感细胞和/或受试者中是否有所不同。尽管关于艾滋病毒-1的传染性、靶细胞内的复制、病毒免疫致病机制(S)以及成人中艾滋病的发展有广泛的文献，但迄今为止还没有发表具体的细胞和/或基于分子的研究来检验艾滋病毒-1在老年受试者或感染艾滋病毒-1的老年患者体内的不同传染性或繁殖。我们实验室的结果表明，年轻人和老年人以及灵长类单个核细胞在病毒生长方面存在显著差异。与年轻捐献者的病毒感染细胞相比，感染HIV-1的老年单个核细胞和淋巴细胞中的病毒滴度增加。我们认为，老化的淋巴细胞可能不太容易受到HIV-1介导的细胞死亡的影响，并可能作为促进病毒粒子产生的储备库。考虑到在各种慢性炎症性疾病状态和衰老中观察到的T细胞表型变化，我们认为老年人循环中的T细胞可能会发生类似的系统性Th2极化，使他们更容易感染HIV-1疾病。基于这些发现，我们正在使用年轻和老年的单核细胞和T淋巴细胞来检测HIV-1介导的信号、复制和免疫病理机制的各种参数。正在进行其他研究，以检测这些受试者循环中的同型半胱氨酸、维生素B12、叶酸和红细胞叶酸水平的变化，以确定这些受试者是否有任何与年龄和HIV相关的变化，以及任何可能与免疫表型和细胞凋亡的相关性。这些信息应该为艾滋病发病机制中与年龄相关的任何差异提供宝贵的信息。最后，我们已经确定了几种新型的趋化因子受体拮抗剂，它们可以阻断几种受体，并能够阻断HIV的感染性和结合以及趋化因子的功能。我们认为这些拮抗剂在艾滋病的治疗中可能具有潜在的治疗价值。