a Division of Infectious Diseases, Department of Pediatrics , University of California San Diego , La Jolla , CA , USA.
b Rady Children's Hospital , San Diego , CA , USA.
Autophagy. 2019 Apr;15(4):744-746. doi: 10.1080/15548627.2019.1569950. Epub 2019 Jan 27.
Despite advances in HIV therapy, there is no cure, and lifelong antiretroviral treatment is required to suppress viral replication. We hypothesized that HIV maintains the survival of latently infected CD4 T cells through increased expression of cell survival factors including XIAP, BIRC2 and BECN1. We found that DIABLO/SMAC mimetics promote the degradation of XIAP and BIRC2 in latent HIV-infected resting memory CD4 T cells (HIV-T) without activating viral transcription. Also in HIV-T, but not in uninfected cells, the degradation of XIAP and BIRC2 leads to the induction of macroautophagy/autophagy, and the formation of a cell death complex on phagophore membranes that consist of autophagy (ATG5, ATG7 and SQSTM1) and pro-apoptotic (FADD, RIPK1, RIPK3, CASP8) proteins. This results in autophagy-dependent apoptosis of HIV-T while sparing uninfected cells. These findings support the potential use of DIABLO/SMAC mimetics as part of an HIV cure strategy. Abbreviations: ART: antiretroviral therapy; ATG2A: autophagy related 2A; ATG2B: autophagy related 2B; ATG5: autophagy related 5; ATG7: autophagy related 7; BCL2: BCL2, apoptosis regulator; BECN1: beclin 1; BIRC2: baculoviral IAP repeat containing 2; CASP8: caspase 8; CFLAR: CASP8 and FADD like apoptosis regulator; DIABLO/SMAC: diablo IAP-binding mitochondrial protein; SM: DIABLO/SMAC mimetics; DISC: death-inducing signaling complex; FADD: Fas associated via death domain; FAS: Fas cell surface death receptor; HIV: human immunodeficiency virus type 1; HIV-T: HIV latent resting central memory CD4 T cells; IAP: inhibitor of apoptosis protein; RIPK1: receptor interacting serine/threonine kinase 1; RIPK3: receptor interacting serine/threonine kinase 3; RNAi: RNA interference; SQSTM1: sequestosome 1; T: resting central memory CD4 T cells; TNF: tumor necrosis factor; TNFSF10: TNF superfamily member 10; XIAP: X-linked inhibitor of apoptosis.
尽管 HIV 治疗取得了进展，但目前仍无法治愈，需要终身接受抗逆转录病毒治疗以抑制病毒复制。我们假设 HIV 通过增加细胞存活因子的表达来维持潜伏感染的 CD4 T 细胞的存活，包括 XIAP、BIRC2 和 BECN1。我们发现，DIABLO/SMAC 模拟物在不激活病毒转录的情况下，促进潜伏感染的 HIV 静止记忆 CD4 T 细胞（HIV-T）中 XIAP 和 BIRC2 的降解。同样在 HIV-T 中，但不在未感染的细胞中，XIAP 和 BIRC2 的降解导致巨自噬/自噬的诱导，以及由自噬（ATG5、ATG7 和 SQSTM1）和促凋亡（FADD、RIPK1、RIPK3、CASP8）蛋白组成的细胞死亡复合物在吞噬体膜上的形成。这导致 HIV-T 的自噬依赖性凋亡，而未感染的细胞则得以幸免。这些发现支持将 DIABLO/SMAC 模拟物用作 HIV 治疗策略的一部分的潜力。缩写：ART：抗逆转录病毒治疗；ATG2A：自噬相关 2A；ATG2B：自噬相关 2B；ATG5：自噬相关 5；ATG7：自噬相关 7；BCL2：BCL2，凋亡调节剂；BECN1：自噬相关蛋白 1；BIRC2：杆状病毒 IAP 重复包含 2；CASP8：半胱氨酸天冬氨酸蛋白酶 8；CFLAR：CASP8 和 FADD 样凋亡调节剂；DIABLO/SMAC：DIABLO IAP 结合线粒体蛋白；SM：DIABLO/SMAC 模拟物；DISC：死亡诱导信号复合物；FADD：死亡域相关 Fas 接头蛋白；FAS：Fas 细胞表面死亡受体；HIV：人类免疫缺陷病毒 1 型；HIV-T：潜伏静止的中央记忆 CD4 T 细胞；IAP：凋亡抑制蛋白；RIPK1：受体相互作用丝氨酸/苏氨酸激酶 1；RIPK3：受体相互作用丝氨酸/苏氨酸激酶 3；RNAi：RNA 干扰；SQSTM1：自噬相关蛋白 1；T：静止的中央记忆 CD4 T 细胞；TNF：肿瘤坏死因子；TNFSF10：TNF 超家族成员 10；XIAP：X 连锁凋亡抑制剂。
