Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations

Gregory M. Laird, C. Korin Bullen, Daniel I.S. Rosenbloom, Alyssa R. Martin, Alison L. Hill, Christine M. Durand, Janet D. Siliciano, Robert F. Siliciano

Research output: Contribution to journalArticlepeer-review

Abstract

Reversal of HIV-1 latency by small molecules is a potential cure strategy. This approach will likely require effective drug combinations to achieve high levels of latency reversal. Using resting CD4+ T cells (rCD4s) from infected individuals, we developed an experimental and theoretical framework to identify effective latency-reversing agent (LRA) combinations. Utilizing ex vivo assays for intracellular HIV-1 mRNA and virion production, we compared 2-drug combinations of leading candidate LRAs and identified multiple combinations that effectively reverse latency. We showed that protein kinase C agonists in combination with bromodomain inhibitor JQ1 or histone deacetylase inhibitors robustly induce HIV-1 transcription and virus production when directly compared with maximum reactivation by T cell activation. Using the Bliss independence model to quantitate combined drug effects, we demonstrated that these combinations synergize to induce HIV-1 transcription. This robust latency reversal occurred without release of proinflammatory cytokines by rCD4s. To extend the clinical utility of our findings, we applied a mathematical model that estimates in vivo changes in plasma HIV-1 RNA from ex vivo measurements of virus production. Our study reconciles diverse findings from previous studies, establishes a quantitative experimental approach to evaluate combinatorial LRA efficacy, and presents a model to predict in vivo responses to LRAs.

Original languageEnglish (US)
Pages (from-to)1901-1912
Number of pages12
JournalJournal of Clinical Investigation
Volume125
Issue number5
DOIs
StatePublished - May 1 2015

ASJC Scopus subject areas

  • Medicine(all)

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