Selection of epigenetically privileged HIV-1 proviruses during treatment with panobinostat and interferon-α2a

Cell. 2024 Feb 29;187(5):1238-1254.e14. doi: 10.1016/j.cell.2024.01.037. Epub 2024 Feb 17.

Abstract

CD4+ T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses.

Keywords: HIV-1; HIV-1 cure; epigenetics; histone acetylation; innate immunity; integration sites; interferon; panobinostat; shock and kill; viral reservoir.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • HIV Infections* / drug therapy
  • HIV-1* / genetics
  • Histone Deacetylase Inhibitors* / therapeutic use
  • Humans
  • Interferon-alpha* / therapeutic use
  • Panobinostat* / therapeutic use
  • Proviruses* / drug effects
  • Virus Latency

Substances

  • Panobinostat
  • Histone Deacetylase Inhibitors
  • peginterferon alfa-2a
  • Interferon-alpha