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Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations
Gregory M. Laird, … , Janet D. Siliciano, Robert F. Siliciano
Gregory M. Laird, … , Janet D. Siliciano, Robert F. Siliciano
Published March 30, 2015
Citation Information: J Clin Invest. 2015;125(5):1901-1912. https://doi.org/10.1172/JCI80142.
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Research Article AIDS/HIV

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

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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.

Authors

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

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Figure 5

Correlation between intracellular and extracellular HIV-1 mRNA after ex vivo LRA treatment.

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Correlation between intracellular and extracellular HIV-1 mRNA after ex ...
Plot of intracellular HIV-1 mRNA copy number against supernatant HIV-1 mRNA copy number after exposure of rCD4s from the same infected individual to treatments containing (circles) or lacking (triangles) a PKC agonist. For PKC agonist–containing treatments, a statistically significant correlation was demonstrated by Tobit regression analysis. P = 0.008, χ2 test. See Methods.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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