The Human Immunodeficiency Virus 1 ASP RNA promotes viral latency by recruiting the Polycomb Repressor Complex 2 and promoting nucleosome assembly

Abstract

Various epigenetic marks at the HIV-1 5′LTR suppress proviral expression and promote latency. Cellular antisense transcripts known as long noncoding RNAs (lncRNAs) recruit the polycomb repressor complex 2 (PRC2) to gene promoters, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), thus promoting nucleosome assembly and suppressing gene expression. We found that an HIV-1 antisense transcript expressed from the 3′LTR and encoding the antisense protein ASP promotes proviral latency. Expression of ASP RNA reduced HIV-1 replication in Jurkat cells. Moreover, ASP RNA expression promoted the establishment and maintenance of HIV-1 latency in Jurkat E4 cells. We show that this transcript interacts with and recruits PRC2 to the HIV-1 5′LTR, increasing accumulation of the suppressive epigenetic mark H3K27me3, while reducing RNA Polymerase II and thus proviral transcription. Altogether, our results suggest that the HIV-1 ASP transcript promotes epigenetic silencing of the HIV-1 5′LTR and proviral latency through the PRC2 pathway.

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

“…Additionally, an antisense transcript originating from the 3 LTR (named the ASP RNA) (Zapata et al, 2017) was recently shown to recruit the PRC2 repressor complex to the HIV-1 5 LTR, increasing the repressive epigenetic mark H3K27me3 while reducing RNAPII occupancy at the viral promoter and promoting the establishment and maintenance of HIV-1 latency at the epigenetic level (Zapata et al, 2017).…”

HIV-1 antisense protein of different clades induces autophagy and associates to the autophagy factor p62

“…A recent study has further underscored the high degree of conservation of this ORF in most HIV-1 clades, but further argued that this gene correlated with the spread of the virus, being less present (or absent) in most SIV, HIV-1 groups N, O and P and less prevalent HIV-1 clades (9). Importantly, a number of previous and more recent studies have further confirmed that antisense transcription overlapping this ORF sequence was detected in transfected and chronically infected cells (10–19).…”

Involvement and Roles of Long Noncoding RNAs in the Molecular Mechanisms of Emerging and Reemerging Viral Infections

“…In addition, several lncRNAs have been reported to regulate gene expression through their interaction with chromatin modifying complexes, especially the polycomb repressor complex 2 (PRC2) that directs methylation marks to the promoters of targeted genes. Similarly, lncRNA ASP RNA was reported to interact with PRC2 at the HIV-1 5 0 LTR region and results in H3K27me3 mark accumulation (Zapata et al, 2017). Along with these findings, ASP RNA reduced RNA polymerase II expression (Zapata et al, 2017).…”

“…Similarly, lncRNA ASP RNA was reported to interact with PRC2 at the HIV-1 5 0 LTR region and results in H3K27me3 mark accumulation (Zapata et al, 2017). Along with these findings, ASP RNA reduced RNA polymerase II expression (Zapata et al, 2017). As a result, HIV-1 replication is repressed and its latency is established and maintained (Zapata et al, 2017).…”

“…Along with these findings, ASP RNA reduced RNA polymerase II expression (Zapata et al, 2017). As a result, HIV-1 replication is repressed and its latency is established and maintained (Zapata et al, 2017). More recently, Postlera et al used a metaanalytic approach to investigate differentially expressed lncRNAs during HIV-1 infection.…”