Molecular mechanisms of HIV latency
Daniele C. Cary, … , Koh Fujinaga, B. Matija Peterlin
Daniele C. Cary, … , Koh Fujinaga, B. Matija Peterlin
Published January 5, 2016
Citation Information: J Clin Invest. 2016;126(2):448-454. https://doi.org/10.1172/JCI80565.
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Molecular mechanisms of HIV latency

Abstract

HIV seeds reservoirs of latent proviruses in the earliest phases of infection. These reservoirs are found in many sites, including circulating cells, the lymphoid system, the brain, and other tissues. The “shock and kill” strategy, where HIV transcription is reactivated so that antiretroviral therapy and the immune system clear the infection, has been proposed as one approach to curing AIDS. In addition to many defective viruses, resting hematopoietic cells harbor transcriptionally latent HIV. Understanding basic mechanisms of HIV gene expression provides a road map for this strategy, allowing for manipulation of critical cellular and viral transcription factors in such a way as to maximize HIV gene expression while avoiding global T cell activation. These transcription factors include NF-κB and the HIV transactivator of transcription (Tat) as well as the cyclin-dependent kinases CDK13 and CDK11 and positive transcription elongation factor b (P-TEFb). Possible therapies involve agents that activate these proteins or release P-TEFb from the inactive 7SK small nuclear ribonucleoprotein (snRNP). These proposed therapies include PKC and MAPK agonists as well as histone deacetylase inhibitors (HDACis) and bromodomain and extraterminal (BET) bromodomain inhibitors (BETis), which act synergistically to reactivate HIV in latently infected cells.

Authors

Daniele C. Cary, Koh Fujinaga, B. Matija Peterlin

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Figure 1

HIV LTR, TFs, and their activation.

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HIV LTR, TFs, and their activation. HIV transcription starts at the TSS,...
HIV transcription starts at the TSS, where the initiator element binds. The compact promoter contains a TATA box and 3 SP1 sites. The enhancer contains overlapping NF-κB and nuclear factor of activated T cells (NF-AT) binding sites (NF-AT sites not shown). The promoter recruits RNAPII. During promoter clearance, CTD Ser5 (red circles) is phosphorylated by CycH/CDK7. P-TEFb is recruited to the HIV LTR via NF-κB (p50/p65 heterodimer), the super elongation complex (SEC), and Tat. Upon recruitment, P-TEFb phosphorylates Ser2. Tat binds to TAR RNA from positions +1 to +60 in all HIV transcripts. Tat and P-TEFb bind to the 5′ bulge and central loop in TAR, respectively. P-TEFb also phosphorylates Spt5 in DSIF and NELF-E, which releases the arrested RNAPII for elongation. PKC or MAPK agonists promote the translocation of NF-κB to the nucleus and increase the synthesis of P-TEFb. LRAs as well as stress (apoptosis, UV light, transcriptional blockers) release P-TEFb from the 7SK snRNP, where P-TEFb is inactivated by HEXIM1. Tyr271 in HEXIM1 binds and occludes the ATP pocket in CDK9. Active CDK9 is phosphorylated on Thr186 in the T loop and Ser175. Note the similarity between TAR and the first stem loop in 7SK snRNA, which allows Tat and HEXIM1 to bind to both structures. Tat also competes with HEXIM1 for P-TEFb. Thus, when sufficient amounts of Tat are made, HIV transcription continues despite increased levels of 7SK snRNP.