Zapata Juan C, Campilongo Federica, Barclay Robert A, DeMarino Catherine, Iglesias-Ussel Maria D, Kashanchi Fatah, Romerio Fabio
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
Laboratory of Molecular Virology, George Mason University, Manassas, VA, USA.
Virology. 2017 Jun;506:34-44. doi: 10.1016/j.virol.2017.03.002. Epub 2017 Mar 21.
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.
HIV-1 5'长末端重复序列（LTR）上的多种表观遗传标记可抑制前病毒表达并促进潜伏。被称为长链非编码RNA（lncRNA）的细胞反义转录本会将多梳抑制复合物2（PRC2）招募至基因启动子，催化组蛋白H3赖氨酸27位点的三甲基化（H3K27me3），从而促进核小体组装并抑制基因表达。我们发现，一种从3'LTR表达并编码反义蛋白ASP的HIV-1反义转录本可促进前病毒潜伏。ASP RNA的表达降低了Jurkat细胞中的HIV-1复制。此外，ASP RNA的表达促进了Jurkat E4细胞中HIV-1潜伏状态的建立和维持。我们表明，该转录本与PRC2相互作用并将其招募至HIV-1 5'LTR，增加抑制性表观遗传标记H3K27me3的积累，同时减少RNA聚合酶II，从而降低前病毒转录。总之，我们的结果表明，HIV-1 ASP转录本通过PRC2途径促进HIV-1 5'LTR的表观遗传沉默和前病毒潜伏。
