Small CD4 Mimetics Prevent HIV-1 Uninfected Bystander CD4 + T Cell Killing Mediated by Antibody-dependent Cell-mediated Cytotoxicity.
Small CD4 Mimetics Prevent HIV-1 Uninfected Bystander CD4 + T Cell Killing Mediated by Antibody-dependent Cell-mediated Cytotoxicity.
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DOI：
10.1016/j.ebiom.2015.12.004
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发表时间：
2016-01
期刊：
影响因子：
11.1
通讯作者：
Finzi A
中科院分区：
文献类型：
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作者：
Richard J;Veillette M;Ding S;Zoubchenok D;Alsahafi N;Coutu M;Brassard N;Park J;Courter JR;Melillo B;Smith AB 3rd;Shaw GM;Hahn BH;Sodroski J;Kaufmann DE;Finzi A
1 型人类免疫缺陷病毒 (HIV-1) 感染会导致 CD4 + T 细胞逐渐耗竭。尽管 CD4 + T 细胞耗竭对于 HIV-1 发病机制很重要，但其确切机制仍不完全清楚。在这里，我们做出了令人惊讶的观察，即抗体依赖性细胞介导的细胞毒性 (ADCC) 介导了 HIV-1 感染细胞培养物中未感染的旁观者 CD4 + T 细胞的死亡。虽然 HIV-1 感染的细胞通过病毒 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 细胞会结合从有效感染细胞中脱落的 gp120，并被 ADCC 介导的抗体有效识别。因此，gp120 脱落代表了一种将 ADCC 反应转向未感染的旁观者 CD4 + T 细胞的病毒机制。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模拟化合物可能在旨在特异性消除HIV-1感染细胞的新策略中具有治疗效用。从有效感染的细胞中脱落的 Gp120 与旁观者 CD4 + T 细胞结合。 Gp120 包被的旁观细胞对 CD4 诱导抗体介导的 ADCC 反应高度敏感。小分子 CD4 模拟物将 CD4 诱导的抗体重定向到 HIV-1 感染的细胞。人类免疫缺陷病毒 1 型 (HIV-1) 感染的标志是 CD4 + T 细胞的逐渐耗竭。使用 HIV-1 感染细胞的培养物，我们观察到病毒用于感染细胞的机制的一部分 (gp120) 与未感染的细胞结合。在感染 gp120 的过程中产生的抗体可以识别未感染的细胞，并将免疫反应重定向到它们，从而消除它们。重要的是，这种现象可以用一种小的 CD4 模拟化合物来阻断，该化合物可以消除 gp120 与未感染细胞的结合，并将免疫系统重新定向到受感染的细胞。
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. Gp120 shed from productively-infected cells binds to bystander CD4 + T cells. Gp120-coated bystander cells are highly sensitivity to ADCC responses mediated by CD4-induced antibodies. Small-molecule CD4-mimetics redirect CD4-induced antibodies to HIV-1-infected cells. The hallmark of human immunodeficiency virus type 1 (HIV-1) infection is the progressive depletion of CD4 + T cells. Using cultures of HIV-1-infected cells, we observed that a part of the machinery that the virus uses to infect cells (gp120) binds to uninfected cells. Antibodies elicited during the course of the infection against the gp120 can recognize uninfected cells and redirect an immune response to them that results in their elimination. Importantly, this phenomenon can be blocked with a small CD4-mimetic compound that abrogates the binding of gp120 to uninfected cells and redirects the immune system to infected cells.