4.8 Article

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

期刊

JOURNAL OF CLINICAL INVESTIGATION
卷 125, 期 5, 页码 1901-1912

出版社

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI80142

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资金

  1. Martin Delaney CARE Collaboratory
  2. Martin Delaney DARE Collaboratory [NIH AI096113, 1U19AI096109]
  3. amFAR [108931-56-RGRL]
  4. Johns Hopkins Center for AIDS Research, NIH [RO143222]
  5. Howard Hughes Medical Institute
  6. NIH [RO143222, DP5OD019851, F31AI116316]

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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.

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