The BAF complex and HIV latency

Abstract

The persistence of a reservoir of transcriptionally competent but latent virus in the presence of antiviral regimens presents the main impediment to a curative therapy against HIV. Therefore it is critical to understand the molecular mechanisms, which lead to the establishment and maintenance of HIV latency, and which contribute to the reversal of this process and mediate HIV transcriptional activation in response to T cell activation signals. Here I discuss features of the nucleosomal landscape of the HIV promoter or 5'LTR in controlling HIV transcription. I emphasize on the emerging understanding of the role of the ATP dependent SWI/SNF chromatin remodelling complexes in modulating the chromatin architecture at the HIV LTR and how this leads to a tight regulation of LTR transcription.

Figure 1. (A) In vivo chromatin organization of the HIV LTR and distribution of putative transcription factor binding sites identified using the TF consite bioinformatics tool. (B) Location of the strictly positioned HIV-1 LTR nucleosomes correlates negatively with the predicted histone binding affinity score (nucleosome score) of the DNA sequence encompassing the HIV LTR. Predicted nucleosome affinity for HIV nucleotide sequence 1–720 was determined using the algorithm described. Means and standard deviations for nucleosome score at insertion sites are indicated by dashed black (mean) and gray (SD) lines and give reference to known genomic sites of HIV integration.

Figure 2. (A) Subunit composition of the two distinct mammalian SWI/SNF complexes, BAF and PBAF. (B) Model for SWI/SNF regulation of HIV LTR transcription. BAF actively counteracts intrinsic histone-DNA sequence preferences within HIV LTR and pulls a preferred nucleosome over DHS1 onto DNA sequences less favorable for nucleosome formation immediately downstream of the TSS, leading to positioning of nuc-1 and transcriptional repression. Upon activation, BAF dissociates from the LTR resulting in de-repression of HIV transcription and expression of Tat. Acetylated Tat selectively recruits the PBAF complex, which actively re-positions nucleosomes formed downstream of TSS enabling efficient transcription elongation.