Regulation of Cell Death in HIV Reservoirs

摘要： 联合抗逆转录病毒治疗可有效抑制HIV-1复制。然而，在这方面， 随着病毒反弹的发展，这种抗逆转录病毒疗法不能清除潜伏的HIV宿主 艾滋病毒感染者在治疗中断后迅速死亡。“震慑”的方法， 消除HIV-1储库的方法是使用潜伏逆转剂和触发剂诱导病毒再活化， 通过病毒介导的细胞病变效应或免疫介导的清除作用导致细胞死亡。然而，在这方面， 潜伏期逆转剂的休克和杀死尚未显示出成功地减少病毒感染。 HIV-1感染者中的病毒库。已有报道，潜伏期逆转剂可以上调 促存活自噬和对抗细胞死亡信号的抗凋亡分子。 抑制这些促生存机制可以促进杀死HIV-1感染的细胞， 在小瓶再激活期间促进杀死HIV-1储库细胞。实验被提议为 检验假设维持HIV-1长期存在的细胞机制 储库对于保护储库细胞免于细胞死亡是重要的，并且靶向这些储库细胞， 细胞机制可使HIV-1储库在病毒再活化期间对细胞死亡敏感：1） 确定HIV-1储库中特异性诱导细胞死亡的机制， 病毒重新激活诱导细胞凋亡和交替性细胞死亡的机制 将测试潜伏逆转剂在潜伏的HIV感染T细胞中的途径; 2）描绘 在病毒再活化时赋予HIV-1储库中细胞死亡抗性的机制; 和3）为了测试靶向促存活机制是否使HIV-1储库细胞对细胞增殖敏感， 在病毒重新激活期间死亡。这些研究将揭示新的分子途径， 有针对性地使HIV-1储库对细胞死亡敏感，并促进开发有效的 清除HIV-1病毒库的方法。

ABSTRACT: The combinational antiretroviral therapy is effective in suppressing HIV-1 replication. However, latent HIV reservoirs cannot be cleared by such antiretroviral therapy, as viral rebound develops rapidly after the treatment is interrupted in people living with HIV. The shock-and-kill approach to eliminate HIV-1 reservoirs is to induce viral reactivation using latency reversal agents and trigger cell death through virus-mediated cytopathic effects or immune-mediated clearance. However, shock-and-kill by latency reversal agents has not been shown to successfully reduce the viral reservoirs in HIV-1 patients. It has been reported that latency reversal agents can up-regulate pro-survival autophagy and anti-apoptotic molecules that counteract cell death signaling. Inhibition of these pro-survival mechanisms can promote the killing of HIV-1-infected cells, and facilitate the killing of HIV-1 reservoir cells during vial re-activation. Experiments are proposed to test hypothesis that cellular mechanisms that maintain the long-term persistence of HIV-1 reservoirs are important for protecting the reservoir cells against cell death, and targeting these cellular mechanisms can sensitize HIV-1 reservoirs to cell death during viral reactivation: 1) To determine the mechanisms for the specific induction of cell death in HIV-1 reservoirs in response to viral reactivation. The mechanisms for the induction of apoptosis and alternative cell death pathways in latent HIV-infected T cells by latency reversal agents will be tested; 2) To delineate the mechanisms that confer the resistance to cell death in HIV-1 reservoirs upon viral reactivation; and 3) To test whether targeting pro-survival mechanisms sensitizes HIV-1 reservoirs cells to cell death during viral re-activation. The studies will reveal novel molecular pathways that could be targeted to sensitize HIV-1 reservoirs to cell death, and facilitate the development of an effective approach to clear HIV-1 reservoirs.