PIWIL4 Maintains HIV-1 Latency by Enforcing Epigenetically Suppressive Modifications on the 5′ Long Terminal Repeat

Abstract

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.

Genomic regions associated withMycoplasma ovipneumoniaepresence in nasal secretions of domestic sheep

“…PIWIL4 , on chromosome 15, has been identified in the chromatin pathway [59, 60], where human PIWIL4 has a role in regulating gene expression in immune cells with gene silencing [61]. In vitro experiments showed that PIWIL4 knockdown in primary human cells from people with HIV-1 on suppressive combined antiretroviral therapy had increased HIV-1 transcription and reversed HIV-1 latency in HIV-1 latently infected Jurkat T cells and primary CD4+ T lymphocytes, as well as resting CD4+ T lymphocytes [62]. Mutations in CUL5 , also located on chromosome 15, have been associated with more rapid loss of CD4+ T cell in HIV infected patients [63].…”

Genes involved in immune, gene translation and chromatin organization pathways associated with Mycoplasma ovipneumoniae presence in nasal secretions of domestic sheep

“…PIWIL4 , on chromosome 15, has been identified in the chromatin pathway [ 67 , 68 ], where human PIWIL4 has a role in regulating gene expression in immune cells with gene silencing [ 69 ]. In vitro experiments showed that PIWIL4 knockdown in primary human cells from people with HIV-1 on suppressive combined antiretroviral therapy had increased HIV-1 transcription and reversed HIV-1 latency in HIV-1 latently infected Jurkat T cells and primary CD4+ T lymphocytes, as well as resting CD4+ T lymphocytes [ 70 ]. Mutations in CUL5 , also located on chromosome 15, have been associated with more rapid loss of CD4+ T cell in HIV infected patients [ 71 ].…”

Identification of CD98 as a Novel Biomarker for HIV-1 Permissiveness and Latent Infection

“…Samples were stored at −80°C until the next step. Finally, proteolytic digests were dissolved into 0.01% formic acid and subjected for nanoscale LC-MS/MS with an EASY-nLC system connected to a Q-Exactive device with higher collisional dissociation fragmentation (Thermo Fisher Scientific) to characterize the differentially expressed proteins among the cell lines as previously described ( 66 ). The LC-MS/MS data were analyzed with PEAKS 6 Studio software (BSI, Canada).…”