Open AccessPIWIL4 Maintains HIV-1 Latency by Enforcing Epigenetically Suppressive Modifications on the 5′ Long Terminal Repeat
Author(s) -
Zhangping He,
Shuliang Jing,
Tao Yang,
Jingliang Chen,
Feng Huang,
Wanying Zhang,
Zhilin Peng,
Bingfeng Liu,
Xiancai Ma,
Liyang Wu,
Ting Pan,
Xu Zhang,
Linghua Li,
Weiping Cai,
Xiaoping Tang,
Junsong Zhang,
Hui Zhang
Publication year - 2020
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.01923-19
Subject(s) - biology , retrotransposon , long terminal repeat , retrovirus , latency (audio) , virus latency , transcription (linguistics) , human immunodeficiency virus (hiv) , suppressor , transcription factor , virology , genetics , gene , microbiology and biotechnology , viral replication , virus , gene expression , mutant , transposable element , linguistics , philosophy , electrical engineering , engineering
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). IMPORTANCE 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.