Abstract
Rebound of HIV viremia after interruption of anti-retroviral therapy is due to the small population of CD4+ T cells that remain latently infected. HIV-1 transcription is the main process controlling post-integration latency. Regulation of HIV-1 transcription takes place at both initiation and elongation levels. Pausing of RNA polymerase II at the 5′ end of HIV-1 transcribed region (5′HIV-TR), which is immediately downstream of the transcription start site, plays an important role in the regulation of viral expression. The activation of HIV-1 transcription correlates with the rearrangement of a positioned nucleosome located at this region. These two facts suggest that the 5′HIV-TR contributes to inhibit basal transcription of those HIV-1 proviruses that remain latently inactive. However, little is known about the cell elements mediating the repressive role of the 5′HIV-TR. We performed a genetic analysis of this phenomenon in Saccharomyces cerevisiae after reconstructing a minimal HIV-1 transcriptional system in this yeast. Unexpectedly, we found that the critical role played by the 5′HIV-TR in maintaining low levels of basal transcription in yeast is mediated by FACT, Spt6, and Chd1, proteins so far associated with chromatin assembly and disassembly during ongoing transcription. We confirmed that this group of factors plays a role in HIV-1 postintegration latency in human cells by depleting the corresponding human orthologs with shRNAs, both in HIV latently infected cell populations and in particular single-integration clones, including a latent clone with a provirus integrated in a highly transcribed gene. Our results indicate that chromatin reassembly factors participate in the establishment of the equilibrium between activation and repression of HIV-1 when it integrates into the human genome, and they open the possibility of considering these factors as therapeutic targets of HIV-1 latency.
Highlights
Following integration into the host cell genome, human immunodeficiency virus (HIV)-1 transcription is the most important step regulating viral replication
We found that the repressive role played by this region is mediated by a group of proteins so far associated with other functions during gene expression
We confirmed that this group of factors plays a role in controlling HIV-1 basal transcription in human cells
Summary
Following integration into the host cell genome, HIV-1 transcription is the most important step regulating viral replication. The main factor involved in this regulation is the viral Tat protein, which binds TAR, a structured RNA element present at the 59 end of the viral mRNAs. The structure of the mRNA 59 end contributes to the pausing of RNA polymerase II (RNApolII) at the LTR [1]. The structure of the mRNA 59 end contributes to the pausing of RNA polymerase II (RNApolII) at the LTR [1] This pausing is characteristic of HIV-1 transcription and appears to play a role in maintaining low levels of basal transcription when the promoter is not activated [2,3]. Tat activates transcription by both inducing chromatin remodeling and recruiting P-TEFb, a cell factor required for productive transcription elongation, onto the viral LTR [4,5]. Induction of the host transcription factors NFa B cooperates with Tat in completing HIV activation [7]
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