Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation.
Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation.
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作者：
尽管进行了抗逆转录病毒治疗（ART），但长期存活的CD 4 + T细胞中潜伏的HIV前病毒的持续存在是病毒根除的主要障碍。由于目前的候选潜伏逆转剂（LRA）诱导HIV转录，但未能清除这些细胞水库，新的方法来杀死这些重新激活的潜伏HIV水库细胞是迫切需要的。HIV潜伏期依赖于整合前病毒的转录静止和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，其使用模式识别受体（PRR）来检测病毒病原体并随后诱导受感染细胞的凋亡。视黄酸诱导基因I（RIG-I）是一类模式识别受体，在识别病毒RNA后介导感染细胞的凋亡和清除。在这里，我们表明，阿维A，FDA批准的视黄酸衍生物，增强RIG-I信号离体，增加HIV转录，并诱导HIV感染细胞的优先凋亡。这些作用通过RIG-I敲低而消除。阿维A还可降低接受抑制性ART的HIV感染受试者的CD 4 + T细胞中的前病毒DNA水平，与辛二酰苯胺异羟肟酸（SAHA）（一种组蛋白去乙酰化酶抑制剂）联合使用可增强这种效应。先天性细胞防御网络的药理学增强可以提供一种消除潜伏HIV库中重新激活的细胞的方法。
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 transcriptional quiescence of the integrated provirus and circumvention of immune defense mechanisms. These defenses include cell-intrinsic innate responses that use pattern-recognition receptors (PRR) to detect viral pathogens and subsequently induce apoptosis of the infected cell. Retinoic acid-inducible gene I (RIG-I) forms one class of pattern-recognition receptors that mediates apoptosis and elimination of infected cells after recognition of viral RNA. Here we show that acitretin, an FDA-approved retinoic-acid derivative, enhances RIG-I signaling ex vivo, increases HIV transcription, and induces preferential apoptosis of HIV-infected cells. These effects are abrogated by RIG-I knockdown. Acitretin also decreases proviral DNA levels in CD4+ T cells from HIV-infected subjects on suppressive ART, an effect amplified by combination with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. Pharmacologic enhancement of an innate cellular defense network could provide a means to eliminate reactivated cells in the latent HIV reservoir.
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通过RIG-I介导的5'-二磷酸RNA识别的抗病毒药免疫。
影响因子：
64.8
作者：
Goubau, Delphine;Schlee, Martin;Deddouche, Safia;Pruijssers, Andrea J.;Zillinger, Thomas;Goldeck, Marion;Schuberth, Christine;Van der Veen, Annemarthe G.;Fujimura, Tsutomu;Rehwinkel, Jan;Iskarpatyoti, Jason A.;Barchet, Winfried;Ludwig, Janos;Dermody, Terence S.;Hartmann, Gunther;Reis e Sousa, Caetano
通讯作者：
Reis e Sousa, Caetano
影响因子：
64.8
作者：
Peisley A;Wu B;Xu H;Chen ZJ;Hur S
通讯作者：
Hur S
DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
11.1
作者：
Chun, TW;Stuyver, L;Fauci, AS
通讯作者：
Fauci, AS
影响因子：
5.4
作者：
Doehle, Brian P.;Hladik, Florian;Gale, Michael, Jr.
通讯作者：
Gale, Michael, Jr.
影响因子：
30.5
作者：
Kawai, T;Takahashi, K;Akira, S
通讯作者：
Akira, S