Article

Repressive LTR nucleosome positioning by the BAF complex is required for HIV latency

Fred Hutchinson Cancer Research Center, United States of America
PLoS Biology (Impact Factor: 11.77). 11/2011; 9(11):e1001206. DOI: 10.1371/journal.pbio.1001206
Source: PubMed

ABSTRACT Persistence of a reservoir of latently infected memory T cells provides a barrier to HIV eradication in treated patients. Several reports have implicated the involvement of SWI/SNF chromatin remodeling complexes in restricting early steps in HIV infection, in coupling the processes of integration and remodeling, and in promoter/LTR transcription activation and repression. However, the mechanism behind the seemingly contradictory involvement of SWI/SNF in the HIV life cycle remains unclear. Here we addressed the role of SWI/SNF in regulation of the latent HIV LTR before and after transcriptional activation. We determined the predicted nucleosome affinity of the LTR sequence and found a striking reverse correlation when compared to the strictly positioned in vivo LTR nucleosomal structure; sequences encompassing the DNase hypersensitive regions displayed the highest nucleosome affinity, while the strictly positioned nucleosomes displayed lower affinity for nucleosome formation. To examine the mechanism behind this reverse correlation, we used a combinatorial approach to determine DNA accessibility, histone occupancy, and the unique recruitment and requirement of BAF and PBAF, two functionally distinct subclasses of SWI/SNF at the LTR of HIV-infected cells before and after activation. We find that establishment and maintenance of HIV latency requires BAF, which removes a preferred nucleosome from DHS1 to position the repressive nucleosome-1 over energetically sub-optimal sequences. Depletion of BAF resulted in de-repression of HIV latency concomitant with a dramatic alteration in the LTR nucleosome profile as determined by high resolution MNase nucleosomal mapping. Upon activation, BAF was lost from the HIV promoter, while PBAF was selectively recruited by acetylated Tat to facilitate LTR transcription. Thus BAF and PBAF, recruited during different stages of the HIV life cycle, display opposing function on the HIV promoter. Our data point to the ATP-dependent BRG1 component of BAF as a putative therapeutic target to deplete the latent reservoir in patients.

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    • "me and by directing this nucleosome from a more favorable predicted position to a position more proximal to the TSS . There is precedent for this model . Recently , derepression of HIV expression was observed upon loss of the human BAF SWI2 / SNF2 subfamily complex activity , which resulted in a re - duction in the occupancy of the +1 nucleosome ( Rafati et al . , 2011 ) . Consistent with the idea that BRM causes increased oc - cupancy and more TSS proximal positioning of the +1 nucleosome at the ABI5 locus , BRM very strongly associated with the region of ABI5 locus occupied by the +1 nucleosome ."
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