Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
J Virol. 2020 May 4;94(10). doi: 10.1128/JVI.01923-19.
Although substantial progress has been made in depicting the molecular pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection, the comprehensive mechanism of HIV-1 latency and the most promising therapeutic strategies to effectively reactivate the HIV-1 latent reservoir to achieve a functional cure for AIDS remain to be systematically illuminated. Here, we demonstrated that piwi (P element-induced Wimpy)-like RNA-mediated gene silencing 4 (PIWIL4) played an important role in suppressing HIV-1 transcription and contributed to the latency state in HIV-1-infected cells through its recruitment of various suppressive factors, including heterochromatin protein 1α/β/γ, SETDB1, and HDAC4. The knockdown of PIWIL4 enhanced HIV-1 transcription and reversed HIV-1 latency in both HIV-1 latently infected Jurkat T cells and primary CD4 T lymphocytes and resting CD4 T lymphocytes from HIV-1-infected individuals on suppressive combined antiretroviral therapy (cART). Furthermore, in the absence of PIWIL4, HIV-1 latently infected Jurkat T cells were more sensitive to reactivation with vorinostat (suberoylanilide hydroxamic acid, or SAHA), JQ1, or prostratin. These findings indicated that PIWIL4 promotes HIV-1 latency by imposing repressive marks at the HIV-1 5' long terminal repeat. Thus, the manipulation of PIWIL4 could be a novel strategy for developing promising latency-reversing agents (LRAs). HIV-1 latency is systematically modulated by host factors and viral proteins. During this process, the suppression of HIV-1 transcription plays an essential role in promoting HIV-1 latency. In this study, we found that PIWIL4 repressed HIV-1 promoter activity and maintained HIV-1 latency. In particular, we report that PIWIL4 can regulate gene expression through its association with the suppressive activity of HDAC4. Therefore, we have identified a new function for PIWIL4: it is not only a suppressor of endogenous retrotransposons but also plays an important role in inhibiting transcription and leading to latent infection of HIV-1, a well-known exogenous retrovirus. Our results also indicate a novel therapeutic target to reactivate the HIV-1 latent reservoir.
虽然在描绘人类免疫缺陷病毒 1 型（HIV-1）感染的分子发病机制方面已经取得了实质性进展，但 HIV-1 潜伏期的全面机制以及最有希望的治疗策略，以有效地重新激活 HIV-1 潜伏库，从而实现艾滋病的功能性治愈，仍有待系统阐明。在这里，我们证明 piwi（P 元素诱导的 Wimpy）样 RNA 介导的基因沉默 4（PIWIL4）通过招募各种抑制因子，包括异染色质蛋白 1α/β/γ、SETDB1 和 HDAC4，在抑制 HIV-1 转录和促进 HIV-1 感染细胞的潜伏状态方面发挥重要作用。PIWIL4 的敲低增强了 HIV-1 的转录，并逆转了 HIV-1 潜伏感染的 Jurkat T 细胞和接受抑制性联合抗逆转录病毒治疗（cART）的 HIV-1 感染个体的静止 CD4 T 淋巴细胞和原始 CD4 T 淋巴细胞中的 HIV-1 潜伏期。此外，在没有 PIWIL4 的情况下，HIV-1 潜伏感染的 Jurkat T 细胞对伏立诺他（丁酰苯类羟肟酸，或 SAHA）、JQ1 或普洛司他的再激活更为敏感。这些发现表明，PIWIL4 通过在 HIV-1 5'长末端重复序列施加抑制性标记来促进 HIV-1 潜伏期。因此，操纵 PIWIL4 可能是开发有前途的潜伏逆转剂（LRA）的一种新策略。HIV-1 潜伏期受到宿主因素和病毒蛋白的系统调节。在这个过程中，抑制 HIV-1 转录在促进 HIV-1 潜伏期方面起着至关重要的作用。在这项研究中，我们发现 PIWIL4 抑制了 HIV-1 启动子活性并维持了 HIV-1 潜伏期。特别是，我们报告 PIWIL4 可以通过与 HDAC4 的抑制活性相关联来调节基因表达。因此，我们已经确定了 PIWIL4 的一个新功能：它不仅是内源性逆转录转座子的抑制剂，而且在抑制转录并导致 HIV-1 的潜伏感染中也起着重要作用，HIV-1 是一种众所周知的外源性逆转录病毒。我们的研究结果还表明了一种新的治疗靶点，以重新激活 HIV-1 潜伏库。
