Author:
Aksenova Marina,Sybrandt Justin,Cui Biyun,Sikirzhytski Vitali,Ji Hao,Odhiambo Diana,Lucius Matthew D.,Turner Jill R.,Broude Eugenia,Peña Edsel,Lizarraga Sofia,Zhu Jun,Safro Ilya,Wyatt Michael D,Shtutman Michael
Abstract
AbstractHIV-1 Associated Neurocognitive Disorder (HAND) is commonly seen in HIV-infected patients. Viral proteins including Tat cause neuronal toxicity and is worsened by drugs of abuse. To uncover potential targets for anti-HAND therapy, we employed a literature mining system, MOLIERE. Here, we validated Dead Box RNA Helicase 3 (DDX3) as a target to treat HAND via a selective DDX3 inhibitor, RK-33. The combined neurotoxicity of Tat protein and cocaine was blocked by RK-33 in rat and mouse cortical cultures. Transcriptome analysis showed that Tat-activated transcripts include makers and regulators of microglial activation, and RK-33 blocked Tat-induced activation of these mRNAs. Elevated production of proinflammatory cytokines was also inhibited by RK-33. These findings show that DDX3 contributes to microglial activation triggered by Tat and cocaine, and DDX3 inhibition shows promise as a therapy for HAND. Moreover, DDX3 may contribute to the pathology of other neurodegenerative diseases with pathological activation of microglia.
Publisher
Cold Spring Harbor Laboratory
Cited by
3 articles.
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