Regulation of Cell Death in HIV Reservoirs

摘要： 联合抗逆转录病毒疗法在抑制HIV-1复制方面是有效的。然而， 随着病毒反弹的发展，这种抗逆转录病毒治疗无法清除潜伏的艾滋病毒宿主 在艾滋病毒携带者的治疗中断后迅速。电击和杀戮的方法 消除HIV-1储存库是使用潜伏期反转剂和触发器来诱导病毒重新激活 通过病毒介导的细胞病变效应或免疫介导的清除而导致的细胞死亡。然而， 潜伏期反转剂的电击和杀灭尚未被证明能成功地减少病毒 HIV-1患者体内的蓄水池。据报道，潜伏期反转剂可以上调 促进生存的自噬和抗凋亡的分子，这些分子抵消了细胞死亡信号。 抑制这些有利于生存的机制可以促进对感染艾滋病毒-1的细胞的杀伤，以及 促进在小瓶重新激活期间杀死HIV-1储存细胞。建议进行实验，以 测试假设，维持HIV-1长期持续的细胞机制 水库对于保护水库细胞不受细胞死亡的影响是重要的，并针对这些 细胞机制可以使HIV-1储存库对病毒重新激活期间的细胞死亡敏感：1) 确定在HIV-1宿主体内特异性诱导细胞死亡的机制 病毒重新激活。诱导细胞凋亡和细胞交替死亡的机制 将测试潜伏期反转剂在潜伏感染艾滋病毒的T细胞中的途径；2)描绘 HIV-1储存体内的细胞死亡抵抗病毒重新激活的机制； 以及3)测试靶向促进生存机制是否使HIV-1储存库细胞对细胞敏感 在病毒重新激活过程中死亡。这些研究将揭示新的分子途径，可能是 有针对性地使艾滋病毒-1宿主对细胞死亡敏感，并促进开发有效的 清理HIV-1病毒宿主的方法。

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.