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CD 4分子以及趋化因子受体进入， 随后感染人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细胞克隆表达显著的 它们表面上的几种趋化因子受体的水平， T细胞运输、脱粒和细胞内钙动员。 一组人Th 1和Th 2克隆差异表达几种不同的 这些T辅助细胞亚群细胞表面的趋化因子受体 这可能有助于它们选择性的T细胞运输到炎症 位点以及介导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Th 0，Th 1， Th 2克隆都能够被各种T-、M-和 HIV-1的双嗜性菌株。 HIV-1感染的Th 1克隆迅速 感染HIV-1;然而，他们也表现出快速（1-5天） 与感染的Th 2克隆相比，Fas介导的体外细胞凋亡（4-21 天）。Th 1细胞表面Fas配体表达增加， 而不是HIV-1感染后的Th 2克隆可能解释了HIV-1感染后 这种CD 4 + T细胞亚群的周转。进一步审查各种 人Th 1和Th 2克隆之间的凋亡信号差异揭示了 所有人的Th 1细胞而不是Th 2细胞都对激活诱导的 细胞死亡（AICD）。此外，大多数人Th 1克隆表达 低水平的抗凋亡蛋白bcl-2， 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Th 2克隆，其中大多数表达高表达， 内源性bcl-2水平对凋亡刺激不太敏感， HIV-1介导的细胞病变效应。因此，保护 来自HIV诱导的细胞死亡的表达bcl-2的T细胞表明， 细胞凋亡不仅有助于HIV感染杀死细胞， 也允许选择性破坏外周中的Th 1细胞 导致全身性Th 2应答。随着艾滋病在老年人群中的传播 在所有新艾滋病病例中， 据推测，从老年人身上获得的T细胞在接下来的时间里， 今年，临床免疫学部分将尝试直接检查 这个问题患者抗凋亡基因表达水平降低 (e.g. bcl-2和bcl-xl），并且对HIV-1的易感性增加。

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.