McCloskey T W, Ott M, Tribble E, Khan S A, Teichberg S, Paul M O, Pahwa S, Verdin E, Chirmule N
Department of Pediatrics, North Shore University Hospital-Cornell University Medical College, Manhasset, NY 11030, USA.
J Immunol. 1997 Jan 15;158(2):1014-9.
Apoptosis has been suggested to be one of the major mechanisms of depletion of CD4+ T cells in HIV-1-infected individuals. Remarkably, HIV-1-infected cells appear protected from apoptosis, whereas bystander cells show increased apoptosis in lymph nodes of infected individuals. In this work, we present evidence that the trans-activating protein of HIV-1, Tat, has a dual role in regulation of apoptosis in T cells. While addition of exogenous Tat protein induced apoptosis in uninfected T cells, T cell clones stably expressing the Tat protein were protected from activation-induced apoptosis. The addition of exogenous Tat potentiated anti-CD3 mAb, anti-Fas IgM mAb, and TNF-alpha-induced apoptosis of T cells. Pretreatment of Tat with anti-Tat Ab abrogated Tat-induced apoptosis, but did not affect anti-Fas IgM Ab-induced apoptosis. Endogenously expressed Tat was analyzed in Jurkat T cell clones transfected with either full-length tat gene (101 amino acids), or in control cells containing an empty vector. The Tat101-transfected clones were resistant to anti-CD3-induced apoptosis, when compared with cells transfected with vector alone. Furthermore, cross-linking of CD4 molecules on T cells with gp160 and anti-gp160 Ab showed markedly decreased apoptosis in Tat101 cells compared with that induced in cells transfected with vector alone. Taken together, our results indicate that HIV-1 Tat can regulate apoptosis that may contribute to the immunopathogenesis of AIDS.
细胞凋亡被认为是HIV-1感染个体中CD4+ T细胞耗竭的主要机制之一。值得注意的是，被HIV-1感染的细胞似乎受到保护而免于凋亡，而旁观者细胞在受感染个体的淋巴结中则表现出凋亡增加。在这项研究中，我们提供证据表明HIV-1的反式激活蛋白Tat在T细胞凋亡调节中具有双重作用。虽然添加外源性Tat蛋白可诱导未感染T细胞凋亡，但稳定表达Tat蛋白的T细胞克隆对激活诱导的凋亡具有抗性。添加外源性Tat可增强抗CD3单克隆抗体、抗Fas IgM单克隆抗体和TNF-α诱导的T细胞凋亡。用抗Tat抗体预处理Tat可消除Tat诱导的凋亡，但不影响抗Fas IgM抗体诱导的凋亡。在转染全长tat基因（101个氨基酸）的Jurkat T细胞克隆或含有空载体的对照细胞中分析内源性表达的Tat。与单独转染载体的细胞相比，转染Tat101的克隆对抗CD3诱导的凋亡具有抗性。此外，用gp160和抗gp160抗体交联T细胞上的CD4分子显示，与单独转染载体的细胞相比，Tat101细胞中的凋亡明显减少。综上所述，我们的结果表明HIV-1 Tat可调节凋亡，这可能有助于艾滋病的免疫发病机制。
