Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells

Lachlan R. Gray, Hung On, Emma Roberts, Hao K. Lu, Michael A. Moso, Jacqueline A. Raison, Catherine Papaioannou, Wan Jung Cheng, Anne M. Ellett, Jonathan C. Jacobson, Damian F.J. Purcell, Steven Wesselingh, Paul R. Gorry, Sharon R. Lewin, Melissa J. Churchill

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.

Original languageEnglish
Pages (from-to)455-463
Number of pages9
JournalJournal of NeuroVirology
Volume22
Issue number4
DOIs
Publication statusPublished or Issued - 1 Aug 2016

Keywords

  • CNS
  • HIV-1
  • Latency
  • Latency-reversing agents
  • Reservoirs
  • Toxicity

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Virology

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