Although the HIV-1 Tat protein is necessary for viral exit from latency, the prevailing view has been that HIV-1 does not encode for an inducer of latency, and that environmental stimuli indirectly control entry into latency. Histone methytransferases (HMTs) contribute to the establishment of viral latency through precise positioning of the nucleosomes Nuc-0 and Nuc-1 on the 5'LTR. The HMT, EZH2—a component of the Polycomb Repressor Complex 2 (PRC2)—plays the dominant role in this process. Two very important and possibly related questions are still open. First, how are Nuc-0 and Nuc-1 precisely and invariably positioned at the 5'LTR irrespective of the site and orientation of HIV-1 integration into the host genome? Second, long non-coding RNAs (lncRNAs) are recognized as key participants in this process by tethering PRC2 to the chromatin. What is the lncRNA that recruits PCR2 to the HIV-1 5'LTR? An attractive hypothesis that would answer both questions is that HIV-1 has evolved the ability to encode for its own lncRNA as an autonomous mechanism to recruit PRC2 to the 5'LTR, and to establish latency regardless of the chromatin context, integration site and orientation into the host genome. We demonstrate that an antisense transcript (AST) encoded in the HIV-1 genome and directed from an antisense promoter within the 3'LTR suppresses HIV-1 expression by recruiting PRC2 to the 5'LTR, and promoting epigenetic modifications that lead to the establishment and maintenance of viral latency. These results suggest that HIV-1 encodes for an lncRNA that acts an inducer of viral latency. In addition, they could guide in designing new therapies aimed at reversing or stabilizing latency by interfering or exploiting AST function.
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