HOST FACTORS RELATING TO HIV INFECTIONS

工作总结：最近的研究表明，HIV-1利用细胞 表面结合的CD4分子以及趋化因子受体进入和 随后感染人类T淋巴细胞。我们的实验室已经证明 人类T细胞和抗原特异性T细胞克隆表达显著 几种趋化因子受体在其表面的水平 T细胞运输、脱颗粒和细胞内钙动员。 人类Th1和Th2克隆的面板差异地表达了几个不同的 这些辅助性T细胞亚群细胞表面的趋化因子受体 这可能会促进他们的T细胞选择性运输到炎症性 以及介导HIV-1选择性进入这些T细胞 子集。然而，尽管趋化因子受体存在这些差异 表达，我们最近的研究表明，人类Th0、Th1和 Th2克隆都能够感染各种T-、M-和 HIV-1双嗜性毒株。感染HIV-1的Th1克隆迅速 感染HIV-1；然而，他们也表现出快速(1-5天) Fas介导的体外细胞凋亡与感染Th2克隆的比较(4-21 天数)。Th1BUT细胞表面Fas配体表达增加 HIV-1感染后非Th2克隆可能可以解释更快的 这个CD4+T细胞亚群的周转率。进一步审查各种不同 人类Th1和Th2克隆细胞的凋亡信号差异 所有的人类Th1细胞而不是Th2细胞都对激活敏感 细胞死亡(AICD)。此外，大多数人类Th1克隆表达了 低水平的抗凋亡蛋白bcl2，使它们更 对各种凋亡刺激以及HIV-1诱导的T细胞敏感 死亡。相比之下，人类Th2克隆，其中大多数表达高水平 内源性bcl2水平，不太容易受到凋亡刺激和 HIV-1介导的细胞病变效应。因此，保护 HIV诱导的细胞死亡中表达bcl2的T细胞提示 细胞凋亡不仅导致艾滋病毒感染导致的细胞死亡，而且可能 也允许选择性地破坏外周的Th1细胞 导致系统性Th2反应。随着艾滋病在老年人口中的出现 数量和占所有新增艾滋病病例的百分比继续增加， 据推测，从老年人那里获得的T细胞在接下来的几年里 今年，临床免疫科将尝试直接检查 这个问题。患者表达的抗凋亡基因水平降低 (如BCL-2和BCL-XL)，并增加对艾滋病毒-1的易感性。

Summary of Work: Recent studies have shown that HIV-1 utilizes cell surface-bound CD4 molecules as well as chemokine receptors to enter and subsequently infect human T lymphocytes. Our laboratory has demonstrated that human T cells and antigen-specific T cell clones express significant levels of several chemokine receptors on their surface which mediate T-cell trafficking, degranulation, and intracellular calcium mobilization. Panels of human Th1 and Th2 clones differentially express several distinct chemokine receptors on the cell surface of these T helper cell subsets which may facilitate their selective T cell trafficking to inflammatory sites as well as mediate the selective entry of HIV-1 into these T cell subsets. However, despite these differences in chemokine receptor expression, our recent studies have demonstrated that human Th0, Th1, and Th2 clones are all capable of being infected with the various T-, M-, and dual-tropic strains of HIV-1. HIV-1-infected Th1 clones are rapidly infected with HIV-1; however, they also exhibit a rapid (1-5 day) Fas-mediated apoptosis in vitro compared to infected Th2 clones (4-21 days). The increased expression of Fas ligand on the surface of Th1 but not Th2 clones post HIV-1 infection may possibly explain the more rapid turnover of this CD4+ T cell subset. Further examination of the various apoptotic signaling differences between human Th1 and Th2 clones revealed that all human Th1 but not Th2 cells are susceptible to activation-induced cell death (AICD). In addition, the majority of human Th1 clones expressed low levels of the anti-apoptotic protein, bcl-2, making them more susceptible to various apoptotic stimuli as well as HIV-1 induced T cell death. In contrast, human Th2 clones, the majority of which express high levels of endogenous bcl-2, were less susceptible to apoptotic stimuli and HIV-1-mediated cytopathic effects. Thus, the protection of bcl-2-expressing T cells from HIV-induced cell death suggests that apoptosis not only contributes to cell killing by HIV infection but may also permit the selective destruction of Th1 cells in the periphery leading to a systemic Th2 response. As AIDS in the elderly population continues to increase in number and as a percentage of all new AIDS cases, it has been hypothesized that T cells obtained from elderly Over the next year, the Clinical Immunology Section will attempt to directly examine this question. patients express decreased levels of anti-apoptotic genes (e.g. bcl-2 and bcl-xl) and have an increases susceptibility to HIV-1.