Cell-to-cell transmission of HIV-1 from provirus-activated cells to resting naïve and memory human primary CD4 T cells is highly efficient and requires CD4 and F-actin but not chemokine receptors.
Cell-to-cell transmission of HIV-1 from provirus-activated cells to resting naïve and memory human primary CD4 T cells is highly efficient and requires CD4 and F-actin but not chemokine receptors.
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DOI：
10.1002/jmv.28005
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发表时间：
2022-11
影响因子：
12.7
通讯作者：
Yu, Qigui
中科院分区：
文献类型：
--
作者：
Lan, Jie;Li, Wei;Yu, Richard;Syed, Fahim;Yu, Qigui
携带具有复制能力的原病毒的潜伏感染细胞是 HIV-1 治愈的主要障碍。清除这些细胞的一项主要努力集中在开发“休克和杀伤”方法，以迫使原病毒重新激活，通过病毒细胞病变效应、宿主免疫反应或两者来诱导细胞杀伤。我们对原病毒重新激活过程中的 HIV-1 蛋白表达、病毒粒子产生和细胞间病毒传播进行了动力学和机制研究。用罗米地辛 (RMD) 或 PMA 刺激的原病毒激活的 ACH-2 细胞早期产生 Nef，然后与病毒粒子的出现同时产生 Env 和 Gag。原病毒激活细胞表面的 Env 和细胞 F-肌动蛋白对于病毒学突触的形成至关重要，从而介导 HIV-1 从原病毒激活细胞到未感染细胞的细胞间传播。这种 HIV-1 细胞间传播比无细胞病毒传播的传播效率要高得多，并且需要 F-肌动蛋白重塑和 CD4，但不需要趋化因子受体。静息的人类原代 CD4+ T 细胞，包括幼稚亚群和记忆亚群，尤其是记忆 CD4+ T 细胞，非常容易通过细胞间传播感染 HIV-1。蛋白酶抑制剂 (PI) 和识别 CD4 结合位点 (CD4b) 的中和抗体 (nAb)（例如 VRC01）可显着减少 HIV-1 从原病毒激活细胞到细胞的传播，但逆转录酶 (RT) 抑制剂恩曲他滨 (FTC) 则不会。因此，我们的结果表明，具有有效阻断能力的PI应在“休克和杀伤”方法的临床应用中使用，最有可能与CD4bs nAb联合使用，以预防新的HIV-1感染。从感染者体内根除 HIV-1 仍然是一项重大的医学挑战。联合抗逆转录病毒治疗 (ART) 显着降低了 HIV-1 相关的发病率和死亡率。然而，ART 无法消除 HIV-1，因为接受 ART 的患者仍有残留病毒血症。持续性病毒血症主要由长寿命潜伏感染细胞中具有复制能力的原病毒引起，这是根除 HIV-1 的主要障碍。清除这些潜伏感染细胞的一项主要努力集中在开发“休克和杀死”方法，以迫使原病毒重新激活以诱导细胞死亡。 “电击和杀灭”方法必须与 ART 结合使用，以防止新的感染。我们研究了 HIV-1 蛋白表达、病毒粒子产生以及原病毒重新激活过程中病毒传播和阻断的动力学和机制事件。我们的结果表明，临床应用的“休克和杀伤”方法的 ART 方案应包含 PI 加 RT 抑制剂，以同时预防和抑制原病毒激活细胞的新感染。
Latently infected cells harboring replication‐competent proviruses represent a major barrier to HIV‐1 cure. One major effort to purge these cells has focused on developing the “shock and kill” approach for forcing provirus reactivation to induce cell killing by viral cytopathic effects, host immune responses, or both. We conducted kinetic and mechanistic studies of HIV‐1 protein expression, virion production, and cell‐to‐cell virus transmission during provirus reactivation. Provirus‐activated ACH‐2 cells stimulated with romidepsin (RMD) or PMA produced Nef early, and then Env and Gag in parallel with the appearance of virions. Env on the surface of provirus‐activated cells and cellular F‐actin were critical in the formation of virological synapses to mediate cell‐to‐cell transmission of HIV‐1 from provirus‐activated cells to uninfected cells. This HIV‐1 cell‐to‐cell transmission was substantially more efficient than transmission seen via cell‐free virus spread and required F‐actin remodeling and CD4, but not chemokine receptors. Resting human primary CD4+ T cells including naïve and memory subpopulations and, especially the memory CD4+ T cells, were highly susceptible to HIV‐1 infection via cell‐to‐cell transmission. Cell‐to‐cell transmission of HIV‐1 from provirus‐activated cells was profoundly decreased by protease inhibitors (PIs) and neutralizing antibodies (nAbs) that recognize the CD4‐binding site (CD4bs) such as VRC01, but not by reverse transcriptase (RT) inhibitor Emtricitabine (FTC). Therefore, our results suggest that PIs with potent blocking abilities should be used in clinical application of the “shock and kill” approach, most likely in combination with CD4bs nAbs, to prevent new HIV‐1 infections. HIV‐1 eradication from infected individuals remains a major medical challenge. Combination antiretroviral therapy (ART) has led to a profound reduction in HIV‐1‐related morbidity and mortality. However, ART fails to eliminate HIV‐1, as patients on ART still have residual viremia. The persistent viremia mainly arises from replication‐competent proviruses in long‐lived latently infected cells, which represent a major obstacle for HIV‐1 eradication. One major effort to purge these latently infected cells has focused on developing the “shock and kill” approach for forcing provirus reactivation to induce cell killing. The “shock and kill” approach must be used with ART to prevent new infections. We studied the kinetic and mechanistic events of HIV‐1 protein expression, virion production, and virus transmission and blockade during provirus reactivation. Our results suggest that ART regimens in clinical application of the “shock and kill” approach should contain PIs plus RT inhibitors to simultaneously prevent and inhibit new infection from provirus‐activated cells.
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影响因子：
6.7
作者：
Josefsson L;Palmer S;Faria NR;Lemey P;Casazza J;Ambrozak D;Kearney M;Shao W;Kottilil S;Sneller M;Mellors J;Coffin JM;Maldarelli F
通讯作者：
Maldarelli F
影响因子：
5.4
作者：
Etemad-Moghadam, B;Sun, Y;Sodroski, J
通讯作者：
Sodroski, J
DOI：
10.1073/pnas.0804192105
发表时间：
2008-10-28
影响因子：
11.1
作者：
Joos, Beda;Fischer, Marek;Guenthard, Huldrych F.
通讯作者：
Guenthard, Huldrych F.
影响因子：
5.4
作者：
Fondere, JM;Petitjean, G;Vendrell, JP
通讯作者：
Vendrell, JP
影响因子：
30.8
作者：
Cameron, EE;Bachman, KE;Baylin, SB
通讯作者：
Baylin, SB