Center for Virology, Burnet Institute, Melbourne, Victoria, Australia.
Virology. 2010 Jan 20;396(2):246-55. doi: 10.1016/j.virol.2009.10.029. Epub 2009 Nov 13.
CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) strains cause CD4+ T-cell loss in most infected individuals, but mechanisms underlying cytopathicity of R5 viruses are poorly understood. We investigated mechanisms contributing to R5 envelope glycoprotein (Env)-mediated cellular apoptosis by constructing a panel of retroviral vectors engineered to co-express GFP and R5 Envs derived from two HIV-1-infected subjects spanning asymptomatic (Early, E-R5 Envs) to late stages of infection (Late, L-R5 Envs). The L-R5 Envs induced significantly more cellular apoptosis than E-R5 Envs, but only in Env-expressing (GFP-positive) cells, and only in cells where CD4 and CCR5 levels were limiting. Studies with fusion-defective Env mutants showed induction of apoptosis required membrane-fusing events. Our results provide evidence for an intracellular mechanism of R5 Env-induced apoptosis of CD4+ cells that requires membrane fusion. Furthermore, they contribute to a better understanding of mechanisms involved in CD4+ T-cell loss in subjects experiencing progressive R5 HIV-1 infection.
CCR5- 使用（R5）人类免疫缺陷病毒 1 型（HIV-1）株在大多数感染个体中导致 CD4+T 细胞丢失，但 R5 病毒细胞病变的机制尚不清楚。我们通过构建一组逆转录病毒载体来研究导致 R5 包膜糖蛋白（Env）介导的细胞凋亡的机制，这些载体被设计为共表达 GFP 和来自两名 HIV-1 感染个体的 R5 Envs，涵盖无症状（早期，E-R5 Envs）到感染晚期（晚期，L-R5 Envs）。与 E-R5 Envs 相比，L-R5 Envs 诱导的细胞凋亡明显更多，但仅在表达 Env（GFP 阳性）的细胞中，并且仅在 CD4 和 CCR5 水平有限的细胞中。与融合缺陷型 Env 突变体的研究表明，诱导凋亡需要膜融合事件。我们的结果为 R5 Env 诱导 CD4+细胞凋亡的细胞内机制提供了证据，该机制需要膜融合。此外，它们有助于更好地理解在经历进行性 R5 HIV-1 感染的个体中 CD4+T 细胞丢失涉及的机制。
