Li Peilin, Kaiser Philipp, Lampiris Harry W, Kim Peggy, Yukl Steven A, Havlir Diane V, Greene Warner C, Wong Joseph K
Infectious Diseases Section, Medical Service, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA.
Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Nat Med. 2016 Jul;22(7):807-11. doi: 10.1038/nm.4124. Epub 2016 Jun 13.
The persistence of latent HIV proviruses in long-lived CD4(+) T cells despite antiretroviral therapy (ART) is a major obstacle to viral eradication. Because current candidate latency-reversing agents (LRAs) induce HIV transcription, but fail to clear these cellular reservoirs, new approaches for killing these reactivated latent HIV reservoir cells are urgently needed. HIV latency depends upon the transcriptional quiescence of the integrated provirus and the circumvention of immune defense mechanisms. These defenses include cell-intrinsic innate responses that use pattern-recognition receptors (PRRs) to detect viral pathogens, and that subsequently induce apoptosis of the infected cell. Retinoic acid (RA)-inducible gene I (RIG-I, encoded by DDX58) forms one class of PRRs that mediates apoptosis and the elimination of infected cells after recognition of viral RNA. Here we show that acitretin, an RA derivative approved by the US Food and Drug Administration (FDA), enhances RIG-I signaling ex vivo, increases HIV transcription, and induces preferential apoptosis of HIV-infected cells. These effects are abrogated by DDX58 knockdown. Acitretin also decreases proviral DNA levels in CD4(+) T cells from HIV-positive subjects on suppressive ART, an effect that is amplified when combined with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. Pharmacological enhancement of an innate cellular-defense network could provide a means by which to eliminate reactivated cells in the latent HIV reservoir.
尽管进行了抗逆转录病毒治疗（ART），潜伏的HIV前病毒仍持续存在于长寿的CD4(+) T细胞中，这是病毒根除的主要障碍。由于目前的候选潜伏逆转剂（LRA）可诱导HIV转录，但无法清除这些细胞储存库，因此迫切需要新的方法来杀死这些重新激活的潜伏HIV储存细胞。HIV潜伏取决于整合前病毒的转录静止以及对免疫防御机制的规避。这些防御包括细胞内在的先天性反应，该反应利用模式识别受体（PRR）来检测病毒病原体，并随后诱导受感染细胞的凋亡。维甲酸（RA）诱导基因I（由DDX58编码的RIG-I）构成一类PRR，其在识别病毒RNA后介导凋亡并消除受感染细胞。在这里，我们表明阿维A，一种经美国食品药品监督管理局（FDA）批准的RA衍生物，在体外增强RIG-I信号传导，增加HIV转录，并诱导HIV感染细胞的优先凋亡。这些效应通过敲低DDX58而消除。阿维A还降低了接受抑制性ART的HIV阳性受试者CD4(+) T细胞中的前病毒DNA水平，当与组蛋白脱乙酰酶抑制剂辛二酰苯胺异羟肟酸（SAHA）联合使用时，这种效应会增强。对先天性细胞防御网络的药理学增强可为消除潜伏HIV储存库中重新激活的细胞提供一种手段。
