HIV Pathogenesis: Differential Effects on Lymphocyte Subsets

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，它在所有年龄的HIV-1感染者中经过长时间的临床潜伏期而发展。与13-49岁的人相比，感染艾滋病毒-1的老年人无艾滋病期较短，预期寿命较短。随着抗逆转录病毒药物和治疗机会性感染的药物等延长生命疗法的出现，在全球范围内观察到艾滋病毒感染后的预期寿命有所延长，1999年50岁以上的艾滋病毒感染者约为5.8亿人，而2020年预计约为10亿人。随着老年人群发病率的增加，确定艾滋病病理、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是很重要的。尽管关于HIV-1的感染性、靶细胞内的复制、病毒免疫发病机制和成人艾滋病的发展有大量文献记载，但迄今为止还没有发表过基于细胞和/或分子的特异性研究，以检查老年受试者或感染HIV-1的老年患者的免疫细胞内HIV-1的任何差异感染性或繁殖。我们实验室的初步结果表明，年轻和年老的单核细胞在病毒生长方面存在显著差异。与来自年轻供者的病毒感染细胞相比，在感染hiv -1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，衰老的淋巴细胞可能对hiv -1介导的细胞死亡不太敏感，并可能作为促进病毒粒子产生的储存库。我们在T-辅助性1 （Th1）与T-辅助性2 （Th2）群体以及转染了Bcl-2和bcl -xl的T细胞中观察到类似的现象。与从同一个体分离的Th2克隆相比，hiv -1感染的Th1克隆表现出更高程度的病毒易感性和死亡率。这种差异活性的部分原因可能是Th1克隆中抗凋亡蛋白bcl-2和bcl-xl的表达较差，以及各种HIV共受体（趋化因子受体）在其细胞表面的表达差异。鉴于在各种慢性炎症疾病状态下观察到的T细胞表型改变，我们认为类似的系统性表型改变可能发生在老年受试者的循环T细胞中，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年老的单核细胞、单核细胞和T淋巴细胞检测hiv -1介导的信号、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感染艾滋病毒的年轻人和老年人受试者，以评估老年患者体内与艾滋病毒感染相关的免疫和生理变化。这些信息应提供有关艾滋病发病机制中与年龄有关的任何差异的宝贵信息。

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.