Division of Infectious Disease and Immune Defence, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
Cell Rep Med. 2023 Sep 19;4(9):101178. doi: 10.1016/j.xcrm.2023.101178. Epub 2023 Aug 30.
HIV-1 persists indefinitely in people living with HIV (PLWH) on antiretroviral therapy (ART). If ART is stopped, the virus rapidly rebounds from long-lived latently infected cells. Using a humanized mouse model of HIV-1 infection and CD4 T cells from PLWH on ART, we investigate whether antagonizing host pro-survival proteins can prime latent cells to die and facilitate HIV-1 clearance. Venetoclax, a pro-apoptotic inhibitor of Bcl-2, depletes total and intact HIV-1 DNA in CD4 T cells from PLWH ex vivo. This venetoclax-sensitive population is enriched for cells with transcriptionally higher levels of pro-apoptotic BH3-only proteins. Furthermore, venetoclax delays viral rebound in a mouse model of persistent HIV-1 infection, and the combination of venetoclax with the Mcl-1 inhibitor S63845 achieves a longer delay in rebound compared with either intervention alone. Thus, selective inhibition of pro-survival proteins can induce death of HIV-1-infected cells that persist on ART, extending time to viral rebound.
HIV-1 在接受抗逆转录病毒治疗 (ART) 的 HIV 感染者 (PLWH) 中会无限期地存在。如果停止 ART，病毒会迅速从寿命较长的潜伏感染细胞中反弹。本研究使用感染 HIV-1 的人源化小鼠模型和接受 ART 的 PLWH 的 CD4 T 细胞，研究了拮抗宿主生存蛋白是否可以促使潜伏细胞死亡并促进 HIV-1 的清除。 Venetoclax 是 Bcl-2 的促凋亡抑制剂，可耗尽接受 ART 的 PLWH 的 CD4 T 细胞中的总和完整 HIV-1 DNA。这种 Venetoclax 敏感的群体富含转录水平更高的促凋亡 BH3-only 蛋白的细胞。此外，Venetoclax 可延迟持续 HIV-1 感染小鼠模型中的病毒反弹，并且 Venetoclax 与 Mcl-1 抑制剂 S63845 的联合使用比单独使用任一干预措施延迟病毒反弹的时间更长。因此，选择性抑制生存蛋白可以诱导在 ART 上持续存在的 HIV-1 感染细胞死亡，从而延长病毒反弹的时间。
