Clearance of HIV-1 or SIV reservoirs by promotion of apoptosis and inhibition of autophagy: Targeting intracellular molecules in cure-directed strategies.
Clearance of HIV-1 or SIV reservoirs by promotion of apoptosis and inhibition of autophagy: Targeting intracellular molecules in cure-directed strategies.
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DOI：
10.1002/jlb.4mr0222-606
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发表时间：
2022-11
影响因子：
5.5
通讯作者：
Wang, Jin
中科院分区：
文献类型：
--
作者：
Chen, Min;Li, Min;Budai, Marietta M.;Rice, Andrew P.;Kimata, Jason T.;Mohan, Mahesh;Wang, Jin
HIV的储存库显示出类似于长寿的免疫记忆细胞的细胞特性，可以用于病毒清除。我们对开发艾滋病毒治疗方法的兴趣源于对感染免疫记忆的研究。我们和其他人已经发现，长寿的免疫记忆细胞采用促生存自噬和抗凋亡机制来保护它们的寿命。在这里，我们描述了一种通过选择性消除携带有复制能力的HIV（SECH）的宿主细胞来清除HIV-1的方法的原理。虽然潜伏期逆转剂（LRA）在宿主细胞中重新激活HIV-1诱导病毒基因表达导致细胞死亡，但LRA也同时上调促生存抗凋亡分子和自噬。从机制上讲，促进HIV-1 LTR指导的基因表达的转录因子，如NF-κB、AP-1和Hif-1α，也可以增强细胞存活和代谢调节所必需的细胞基因的表达，包括Bcl-xL、Mcl-1和自噬基因。在SECH方法中，我们抑制LRA诱导的促存活抗凋亡分子和自噬，从而允许诱导的HIV-1蛋白最大限度地杀死宿主细胞。SECH治疗清除了体内人源化小鼠和体外HIV-1患者PBMC中的HIV-1感染。SECH还清除恒河猴PBMC中SIV的离体感染。目前正在进行研究工作，以提高SECH的疗效和安全性，并促进SECH作为治疗艾滋病毒感染者的治疗方法的发展。
The reservoirs of the HIV display cellular properties resembling long-lived immune memory cells that could be exploited for viral clearance. Our interest in developing a cure for HIV stems from the studies of immunologic memory against infections. We and others have found that long-lived immune memory cells employ prosurvival autophagy and antiapoptotic mechanisms to protect their longevity. Here, we describe the rationale for the development of an approach to clear HIV-1 by selective elimination of host cells harboring replication-competent HIV (SECH). While reactivation of HIV-1 in the host cells with latency reversing agents (LRAs) induces viral gene expression leading to cell death, LRAs also simultaneously up-regulate prosurvival antiapoptotic molecules and autophagy. Mechanistically, transcription factors that promote HIV-1 LTR-directed gene expression, such as NF-κB, AP-1, and Hif-1α, can also enhance the expression of cellular genes essential for cell survival and metabolic regulation, including Bcl-xL, Mcl-1, and autophagy genes. In the SECH approach, we inhibit the prosurvival antiapoptotic molecules and autophagy induced by LRAs, thereby allowing maximum killing of host cells by the induced HIV-1 proteins. SECH treatments cleared HIV-1 infections in humanized mice in vivo and in HIV-1 patient PBMCs ex vivo. SECH also cleared infections by the SIV in rhesus macaque PBMCs ex vivo. Research efforts are underway to improve the efficacy and safety of SECH and to facilitate the development of SECH as a therapeutic approach for treating people with HIV.