Abstract
Intensive antiretroviral therapy successfully suppresses viral replication but is unable to eradicate the virus. HIV persists in a small number of resting memory T cells where HIV has been transcriptionally silenced. This review will focus on recent insights into the HIV transcriptional control mechanisms that provide the biochemical basis for understanding latency. There are no specific repressors of HIV transcription encoded by the virus, instead latency arises when the regulatory feedback mechanism driven by HIV Tat expression is disrupted. Small changes in transcriptional initiation, induced by epigenetic silencing, lead to profound restrictions in Tat levels and force the entry of proviruses into latency. In resting memory T cells, which carry the bulk of the latent viral pool, additional restrictions, especially the limiting cellular levels of the essential Tat cofactor P-TEFb and the transcription initiation factors NF-κB and NFAT ensure that the provirus remains silenced unless the host cell is activated. The detailed understanding of HIV transcription is providing a framework for devising new therapeutic strategies designed to purge the latent viral pool. Importantly, the recognition that there are multiple restrictions imposed on latent proviruses suggest that proviral reactivation will not be achieved when only a single reactivation step is targeted and that any optimal activation strategy will require both removal of epigenetic blocks and the activation of P-TEFb.
Highlights
Intensive antiretroviral therapy successfully suppresses viral replication but is unable to eradicate the virus
The multiple restrictions imposed on latent proviruses that need to be overcome suggest that efficient proviral reactivation will be achieved only if there is the simultaneous removal of multiple blocks to transcription initiation and elongation
Mutation of the NF-B sites results in only a modest inhibition of virus growth in most transformed cell lines [32], signaling through the viral enhancer is essential in order to re-activate latent proviruses and support virus replication in primary T-cells, regardless of whether it is stimulated by NF-B or by NFAT [33,34,35,36,37]
Summary
HIV-1, in common with all other retroviruses uses its long terminal repeat (LTR) as the viral promoter (Fig. 1). The HIV-1 promoter is a powerful and highly optimized transcription machine comprised of three tandem SP1 binding sites [22], an efficient TATA element [23] and a highly active initiator sequence [24]. Each of these elements participates in the co-operative binding of the initiation factor TFIID and its associated TAF co-factors to the TATA element [25] (Fig. 2). In addition to the core promoter, HIV-1 utilizes a signal-responsive "enhancer region" which contains two NFB binding motifs [26].
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