In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4-mediated killing of uninfected CD4 T cells
In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4-mediated killing of uninfected CD4 T cells
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DOI：
10.1128/jvi.77.10.5846-5854.2003
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发表时间：
2003-05-01
影响因子：
5.4
通讯作者：
Goldsmith, MA
中科院分区：
文献类型：
--
作者：
Jekle, A;Kepler, OT;Goldsmith, MA
通过CD 4 T细胞的进行性损失对免疫系统的破坏是艾滋病的标志。CCR 5依赖型（R5）人类免疫缺陷病毒1型（HIV-1）分离株在HIV-1感染的早期无症状阶段占主导地位，而CXCR 4依赖型（X4）分离株通常出现在晚期阶段，通常与CD 4 T细胞的快速下降相一致。体内淋巴细胞杀伤主要通过凋亡发生，但HIV-1感染细胞的凋亡相对于未感染的旁观者细胞的凋亡的重要性是有争议的。在这里，我们表明，在人体淋巴组织离体，未感染的旁观者的CD 4 T细胞的凋亡是一个主要的机制，淋巴细胞耗竭引起的X4 HIV-1菌株，但只是一个次要的机制耗竭R5菌株。此外，X4 HIV-1诱导的旁观者细胞凋亡需要病毒包膜糖蛋白gp 120与CD 4 T细胞上的CXCR 4辅助受体的相互作用。这些结果强调了旁观者细胞凋亡对HIV-1细胞毒性的贡献，并表明与HIV疾病中的辅助受体开关相关，T细胞杀伤从感染限制阶段演变为涉及高度旁观者细胞凋亡的全身毒性。
The destruction of the immune system by progressive loss of CD4 T cells is the hallmark of AIDS. CCR5-dependent (R5) human immunodeficiency virus type 1 (HIV-1) isolates predominate in the early, asymptomatic stages of HIV-1 infection, while CXCR4-dependent (X4) isolates typically emerge at later stages, frequently coinciding with a rapid decline in CD4 T cells. Lymphocyte killing in vivo primarily occurs through apoptosis, but the importance of apoptosis of HIV-1-infected cells relative to apoptosis of uninfected bystander cells is controversial. Here we show that in human lymphoid tissues ex vivo, apoptosis of uninfected bystander CD4 T cells is a major mechanism of lymphocyte depletion caused by X4 HIV-1 strains but is only a minor mechanism of depletion by R5 strains. Further, X4 HIV-1-induced bystander apoptosis requires the interaction of the viral envelope glycoprotein gp120 with the CXCR4 coreceptor on CD4 T cells. These results emphasize the contribution of bystander apoptosis to HIV-1 cytotoxicity and suggest that in association with a coreceptor switch in HIV disease, T-cell killing evolves from an infection-restricted stage to generalized toxicity that involves a high degree of bystander apoptosis.