HIV Pathogenesis: Differential Effects on Lymphocyte Sub

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。随着延长生命疗法的出现，如针对机会性感染的抗逆转录病毒药物，全世界在接触艾滋病毒后的预期寿命有所增加，1999年约有5.8亿50岁以上的艾滋病毒感染者，而预计到2020年约有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。我们实验室的结果表明，年轻和老年人和灵长类动物单核细胞之间的病毒生长存在显着差异。与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。考虑到在各种慢性炎症性疾病状态和衰老中观察到的T细胞表型改变，我们认为老年受试者的循环T细胞中可能发生类似的全身性Th 2极化，使其更容易感染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和T淋巴细胞研究HIV-1介导的信号传导、复制和免疫发病机制的各种参数。正在进行其他研究，检查这些受试者的循环同型半胱氨酸，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年龄和HIV相关的变化以及与免疫表型和细胞凋亡的任何可能的相关性。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。最后，我们已经确定了几种新的和新颖的趋化因子受体拮抗剂，阻断几种受体，并能够阻断HIV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。

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.