Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
EBioMedicine. 2015 Dec 9;3:122-134. doi: 10.1016/j.ebiom.2015.12.004. eCollection 2016 Jan.
Human immunodeficiency virus type 1 (HIV-1) infection causes a progressive depletion of CD4 + T cells. Despite its importance for HIV-1 pathogenesis, the precise mechanisms underlying CD4 + T-cell depletion remain incompletely understood. Here we make the surprising observation that antibody-dependent cell-mediated cytotoxicity (ADCC) mediates the death of uninfected bystander CD4 + T cells in cultures of HIV-1-infected cells. While HIV-1-infected cells are protected from ADCC by the action of the viral Vpu and Nef proteins, uninfected bystander CD4 + T cells bind gp120 shed from productively infected cells and are efficiently recognized by ADCC-mediating antibodies. Thus, gp120 shedding represents a viral mechanism to divert ADCC responses towards uninfected bystander CD4 + T cells. Importantly, CD4-mimetic molecules redirect ADCC responses from uninfected bystander cells to HIV-1-infected cells; therefore, CD4-mimetic compounds might have therapeutic utility in new strategies aimed at specifically eliminating HIV-1-infected cells.
人类免疫缺陷病毒 1 型（HIV-1）感染导致 CD4+T 细胞逐渐耗竭。尽管其对 HIV-1 发病机制非常重要，但 CD4+T 细胞耗竭的确切机制仍不完全清楚。在这里，我们惊奇地观察到抗体依赖的细胞介导的细胞毒性（ADCC）介导了 HIV-1 感染细胞培养中未感染旁观者 CD4+T 细胞的死亡。虽然 HIV-1 感染细胞通过病毒 Vpu 和 Nef 蛋白的作用而免受 ADCC 的影响，但未感染的旁观者 CD4+T 细胞结合从有效感染细胞释放的 gp120，并被 ADCC 介导的抗体有效识别。因此，gp120 的脱落代表了一种病毒机制，将 ADCC 反应转向未感染的旁观者 CD4+T 细胞。重要的是，CD4 模拟分子将 ADCC 反应从未感染的旁观者细胞重定向到 HIV-1 感染的细胞；因此，CD4 模拟化合物在旨在特异性消除 HIV-1 感染细胞的新策略中可能具有治疗用途。
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