潜伏者HIV的危机

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艾滋病病毒潜伏是目前研究的热点之一。约翰·霍普金斯大学医学院教授
Robert Siliciano带领他的小组最近在新的一期Journal of Clinical Investigation (JCI)发表了药物激活病毒潜伏的研究。该研究表明通过两种药物的不同组合可以在一定程度上激活潜伏病毒，而且部分组合在激活病毒的基础上，并不会引起炎症反应。他们又通过建立实验模型来预测病人体内病毒RNA量(in vivo)和加入药物激活释放病毒量(ex vivo)之间的关系。


J Clin Invest. 2015 Mar 30. pii: 80142. doi: 10.1172/JCI80142. [Epub ahead of print]
Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations.

Laird GM, Bullen CK, Rosenbloom DI, Martin AR, Hill AL, Durand CM, Siliciano JD, Siliciano RF.


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-1transcription. 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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