Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators

Enrico Palermo, Chiara Acchioni, Daniele Di Carlo, Alessandra Zevini, Michela Muscolini, Matteo Ferrari, Luciano Castiello, Sara Virtuoso, Alessandra Borsetti, Guido Antonelli, Ombretta Turriziani, Marco Sgarbanti, John Hiscott

Research output: Contribution to journalArticlepeer-review

Abstract

The presence of T cell reservoirs in which human immunodeficiency virus (HIV) establishes latency by integrating into the host genome represents a major obstacle to an HIV cure and has prompted the development of strategies aimed at the eradication of HIV from latently infected cells. The "shock-and-kill" strategy is one of the most pursued approaches to the elimination of viral reservoirs. Although several latency-reversing agents (LRAs) have shown promising reactivation activity, they have failed to eliminate the cellular reservoir. In this study, we evaluated a novel immune system-mediated approach to clearing the HIV reservoir, based on a combination of innate immune stimulation and epigenetic reprogramming. The combination of the STING agonist cGAMP (cyclic GMP-AMP) and the FDA-approved histone deacetylase inhibitor resminostat resulted in a significant increase in HIV proviral reactivation and specific apoptosis in HIV-infected cells in vitro Reductions in the proportion of HIV-harboring cells and the total amount of HIV DNA were also observed in CD4+ central memory T (TCM) cells, a primary cell model of latency, where resminostat alone or together with cGAMP induced high levels of selective cell death. Finally, high levels of cell-associated HIV RNA were detected ex vivo in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from individuals on suppressive antiretroviral therapy (ART). Although synergism was not detected in PBMCs with the combination, viral RNA expression was significantly increased in CD4+ T cells. Collectively, these results represent a promising step toward HIV eradication by demonstrating the potential of innate immune activation and epigenetic modulation for reducing the viral reservoir and inducing specific death of HIV-infected cells.IMPORTANCE One of the challenges associated with HIV-1 infection is that despite antiretroviral therapies that reduce HIV-1 loads to undetectable levels, proviral DNA remains dormant in a subpopulation of T lymphocytes. Numerous strategies to clear residual virus by reactivating latent virus and eliminating the reservoir of HIV-1 (so-called "shock-and-kill" strategies) have been proposed. In the present study, we use a combination of small molecules that activate the cGAS-STING antiviral innate immune response (the di-cyclic nucleotide cGAMP) and epigenetic modulators (histone deacetylase inhibitors) that induce reactivation and HIV-infected T cell killing in cell lines, primary T lymphocytes, and patient samples. These studies represent a novel strategy for HIV eradication by reducing the viral reservoir and inducing specific death of HIV-infected cells.

Original languageEnglish
JournalJournal of Virology
Volume93
Issue number21
DOIs
Publication statusPublished - Nov 1 2019

Keywords

  • CD4-Positive T-Lymphocytes/immunology
  • Epigenesis, Genetic
  • Gene Expression Regulation, Viral
  • HIV Infections/genetics
  • HIV-1/immunology
  • Histone Deacetylase Inhibitors/pharmacology
  • Humans
  • Hydroxamic Acids/pharmacology
  • Immunity, Innate/immunology
  • Leukocytes, Mononuclear/drug effects
  • Sulfonamides/pharmacology
  • Virus Activation/immunology
  • Virus Latency/immunology
  • Virus Replication

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