Synergistic Activation of Human Immunodeficiency Virus Type 1 Promoter Activity by NF-κB and Inhibitors of Deacetylases: Potential Perspectives for the Development of Therapeutic Strategies

TLDR

NF‑κB is a key regulator of HIV‑1 transcription, and deacetylase inhibitors such as trichostatin A or sodium butyrate markedly enhance LTR‑driven transcription. The study aims to develop therapeutic strategies that eliminate latent HIV reservoirs by inducing viral expression. TSA and sodium butyrate delay the cytoplasmic recovery of IκBα, prolonging NF‑κB nuclear presence and DNA binding. TSA and sodium butyrate synergize with NF‑κB to strongly activate the HIV‑1 LTR across subtypes A–G, with the effect scaling with κB site number, and this synergy boosts viral replication in both acutely and latently infected cells.

Abstract

ABSTRACT The transcription factor NF-κB plays a central role in the human immunodeficiency virus type 1 (HIV-1) activation pathway. HIV-1 transcription is also regulated by protein acetylation, since treatment with deacetylase inhibitors such as trichostatin A (TSA) or sodium butyrate (NaBut) markedly induces HIV-1 transcriptional activity of the long terminal repeat (LTR) promoter. Here, we demonstrate that TSA (NaBut) synergized with both ectopically expressed p50/p65 and tumor necrosis factor alpha/SF2 (TNF)-induced NF-κB to activate the LTR. This was confirmed for LTRs from subtypes A through G of the HIV-1 major group, with a positive correlation between the number of κB sites present in the LTRs and the amplitude of the TNF-TSA synergism. Mechanistically, TSA (NaBut) delayed the cytoplasmic recovery of the inhibitory protein IκBα. This coincided with a prolonged intranuclear presence and DNA binding activity of NF-κB. The physiological relevance of the TNF-TSA (NaBut) synergism was shown on HIV-1 replication in both acutely and latently HIV-infected cell lines. Therefore, our results open new therapeutic strategies aimed at decreasing or eliminating the pool of latently HIV-infected reservoirs by forcing viral expression.