Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation

Brice J Albert,George B Kyei,Alexander B Barnes,Paul A Wender,Austin Niu,Robert M Williams,Garland R Marshall,Rashmi Ramani,Lee Ratner

doi:10.1038/s41598-017-07814-4

Abstract

Current antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through the administration of synergistic combinations of latency reversing agents (LRAs), such as histone deacetylase (HDAC) inhibitors and protein kinase C (PKC) modulators, provides a promising strategy to reduce if not eradicate the viral reservoir. Here, we demonstrate that largazole and its analogues are isoform-targeted histone deacetylase inhibitors and potent LRAs. Significantly, these isoform-targeted HDAC inhibitors synergize with PKC modulators, namely bryostatin-1 analogues (bryologs). Implementation of this unprecedented LRA combination induces HIV-1 reactivation to unparalleled levels and avoids global T-cell activation within resting CD4+ T-cells.

Highlights

Viral latency in resting CD4+ T-cells remains the most important obstacle to reduction of the latent HIV reservoir in infected patients on anti-retroviral therapy (ART)[1,2,3]
We assayed several compounds, developed through virtual screening to be isoform-targeted Histone deacetylase (HDAC) inhibitors, for their ability to reactivate HIV from latency[42]. These HDAC inhibitors are comprised of a zinc binding group linked to a headgroup which interacts with amino acid residues at the edge of the inhibitor binding cavity of the HDAC42
Most of the current leading HDAC inhibitors affect many, if not all, of the eight zinc-based HDAC isoforms making it difficult to ascertain which HDACs are responsible for promoting HIV-1 latency

Summary

Introduction

Viral latency in resting CD4+ T-cells remains the most important obstacle to reduction of the latent HIV reservoir in infected patients on anti-retroviral therapy (ART)[1,2,3]. Given that newly designed and more synthetically accessible analogues of bryostatin-1 (bryologs) show better efficacy and tolerability as LRAs than the natural product itself in vitro and in animal models, we show that largazoles display remarkable synergy when used in combination with bryologs (Fig. 1)[31,32,33] This unprecedented LRA combination of bryologs together with largazole induces unparalleled levels of HIV expression and avoids global T-cell activation and cytokine release, making this combination a potentially strong therapeutic candidate for preclinical advancement

Methods

Results

Conclusion