AP‐1 and NF‐κB synergize to transcriptionally activate latent HIV upon T‐cell receptor activation

Abstract

Latent HIV‐1 proviruses are capable of reactivating productive lytic infection, but the precise molecular mechanisms underlying emergence from latency are poorly understood. In this study, we determined the contribution of the transcription factors NF‐κB, NFAT, and AP‐1 in the reactivation of latent HIV following T‐cell receptor (TCR) activation using Jurkat T‐cell clones harboring single latent HIV proviruses. Our findings demonstrate that during reactivation from latency, NF‐κB enhances HIV transcription while NFAT inhibits it by competing with NF‐κB for overlapping binding sites on the HIV long terminal repeat (LTR). We have also demonstrated for the first time the molecular contribution of AP‐1 in the reactivation of HIV from latency, whereby AP‐1 synergizes with NF‐κB to regulate HIV transcriptional elongation following TCR activation.

Infectious RNA: Human Immunodeficiency Virus (HIV) Biology, Therapeutic Intervention, and the Quest for a Vaccine

“…The HIV-1 provirus utilizes the host transcription machinery. Host transcription factors such as NF-κB, specificity protein 1 (Sp1) and activator protein 1 (AP-1) are known activators of HIV transcription [50,51,54]. General transcription factors, mediator, and RNA polymerase II (RNA Pol II) assemble into the preinitiation complex at the 5 -LTR promoter.…”

Human Immunodeficiency Virus Type-1 (HIV-1) Transcriptional Regulation, Latency and Therapy in the Central Nervous System

“…They observed that, in the crystal structure, the role of Tat is three-fold-namely, scaffolding and stabilization of the Tat-TAR recognition motif (TRM), making specific interactions through its zinc-coordinating loop and making electrostatic interactions through its arginine-rich motif (ARM). Interestingly, most recently, Hokello et al [23] demonstrated that the cellular transcription factor, activator protein-1 (AP-1), synergizes with NF-κB to regulate HIV transcriptional elongation following T-cell receptor activation.…”

Crossroads of Drug Abuse and HIV Infection: Neurotoxicity and CNS Reservoir

“…Recent evidence has shown that unintegrated HIV can also produce viral proteins, which exacerbate the host immune response and lead to excessive toxicity and cell death [9]. Hence, to make ART more effective, research efforts have been diverted to identify the mechanisms through which latent HIV can be reactivated before being targeted by antiretrovirals [9][10][11][12][13]. Latency reversal agents such as romidepsin, JQ-1, and panobinostat have effectively reactivated the peripheral latent viral reservoir.…”