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Review
. 2013 Mar 21;5(3):902-27.
doi: 10.3390/v5030902.

Lost in transcription: molecular mechanisms that control HIV latency

Ran Taube  1 , Matija Peterlin
Affiliations
Review

Lost in transcription: molecular mechanisms that control HIV latency

Ran Taube et al. Viruses. .

Abstract

Highly active antiretroviral therapy (HAART) has limited the replication and spread of the human immunodeficiency virus (HIV). However, despite treatment, HIV infection persists in latently infected reservoirs, and once therapy is interrupted, viral replication rebounds quickly. Extensive efforts are being directed at eliminating these cell reservoirs. This feat can be achieved by reactivating latent HIV while administering drugs that prevent new rounds of infection and allow the immune system to clear the virus. However, current approaches to HIV eradication have not been effective. Moreover, as HIV latency is multifactorial, the significance of each of its molecular mechanisms is still under debate. Among these, transcriptional repression as a result of reduced levels and activity of the positive transcription elongation factor b (P-TEFb: CDK9/cyclin T) plays a significant role. Therefore, increasing levels of P-TEFb expression and activity is an excellent strategy to stimulate viral gene expression. This review summarizes the multiple steps that cause HIV to enter into latency. It positions the interplay between transcriptionally active and inactive host transcriptional activators and their viral partner Tat as valid targets for the development of new strategies to reactivate latent viral gene expression and eradicate HIV.

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Figures

Figure 1
Figure 1
Epigenetic control modulates HIV latency. A) In activated T cells, levels of transcription factors (NFκB and NFAT) are elevated, which increases rates of HIV transcription. NFκB (p50/RelA) is tethered to the HIV LTR and recruits P-TEFb, HATs and the SWI/SNF remodeling machinery. This leads to an overall de-compaction of chromatin and higher accessibility for other transcription factors. B) Upon entering the resting state, low levels of transcription factors, NFκB, NFAT and co-activators, P-TEFb, decrease HIV transcription. They also reduce levels of Tat. Epigenetic modifications in the form of de-acetylation of histones as well as methylation of histones and DNA increase the compaction of chromatin and contribute to repression of HIV gene expression. The polycomb repressive complex-2 (PRC2) mediates methylation of histones and DNA, thus inducing gene silencing. HDACs are recruited via p50 homodimers, CBF-1, YY1, AP4, and/or COUP-TF-interacting protein 2 (CTIP2).
Figure 2
Figure 2
TI promotes HIV latency. HIV provirus integrates into actively transcribed genes where chromatin is de-compacted and DNA is accessible to the transcriptional machinery. However, this location also leads to the competition between the integrated viral and host promoters, resulting in transcriptional interference (TI). The provirus integrates in the same or opposite polarity to its host gene. Either way, transcription that initiates from the host gene displaces transcription factors that assemble on the HIV LTR, leading to the silencing of proviral gene expression. In the sense orientation, RNAPII terminates in the 5’ HIV LTR and displaces transcription factors (Sp1/TAFs) (upper panel). In the antisense orientation, transcription factors are displaced from both HIV LTRs; extended antisense HIV transcripts are generated and degraded in infected cells (lower panel).
Figure 3
Figure 3
Interplay between positive and negative complexes regulates P-TEFb transcriptional activity. In resting cells, the binding of CycT1 to HEXIM1 in the 7SK snRNP inactivates the kinase activity of P-TEFb. In conjunction with low expression levels of P-TEFb and basal transcription factors, transcription is repressed. Activation of CD4+ T-cells or monocytes increases the expression and kinase activity of P-TEFb. Indicated stress signals release P-TEFb from its inactive complex and subsequently lead to its recruitment to the HIV LTR as an active complex, which stimulates transcription elongation. Low levels of specific miRNA that target CycT1 also contribute to P-TEFb activation and cell proliferation. By releasing Brd4 from chromatin, I-BET or JQ1 liberate P-TEFb from the 7SK snRNP and stimulate HIV transcription.
Figure 4
Figure 4
Recruitment mechanisms of P-TEFb to promoter. The efficient transcription of signal-inducible genes relies on the release of P-TEFb from its inactive complex and also on its recruitment to promoters. Recruitment of P-TEFb to viral and host promoters leads to stimulation of transcription, thus releasing RNAPII from pausing. Several pathways exist for the recruitment of P-TEFb to the HIV LTR. Among them, Tat-independent basal transcription includes recruitment via NFκB, Brd4 and SEC in the Mediator. Elongation of transcription is enhanced by Tat, which binds P-TEFb and tethers it to TAR. (i)Basal transcription from the HIV LTR is maintained by P-TEFb that is recruited to target genes via Brd4 and SEC in the Mediator, which is part of the RNAPII holoenzyme. Herein, Med26 or Cdk8 tether SEC to the Mediator. Within SEC, AFF4 binds to CycT1 and acts as a scaffold that connects P-TEFb to ELL2, which also stimulates transcription. In ENL/AF9 of SEC, the YEATS motif binds RNAPII-associated factor 1 (PAF1) complex and is also recruited to RNAPII in chromatin. P-TEFb may be also recruited to the promoter via Brd4 in the Mediator. This interaction involves tri-acetylated CycT1 and is mediated by the P-TEFb interacting domain (PID) in the C-terminal region of Brd4 and the second bromodomain in Brd4 (BDII). Additionally, the BDII domain of Brd4 associates with acetylated chromatin. However, this interaction does not include active P-TEFb. (ii) P-TEFb is also recruited to the HIV promoter in a Tat-independent mechanism. NFκB binds to DNA, tethers CycT1 to the LTR and increases rates of initiation and elongation of transcription. SEC binds to P-TEFb and is in the same complex.
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