TY - JOUR T1 - Inhibition of the Dead Box RNA Helicase 3 prevents HIV-1 Tat and cocaine-induced neurotoxicity by targeting microglia activation JF - bioRxiv DO - 10.1101/591438 SP - 591438 AU - Marina Aksenova AU - Justin Sybrandt AU - Biyun Cui AU - Vitali Sikirzhytski AU - Hao Ji AU - Diana Odhiambo AU - Mathew D. Lucius AU - Jill R. Turner AU - Eugenia Broude AU - Edsel Peña AU - Sofia Lizzaraga AU - Jun Zhu AU - Ilya Safro AU - Michael D Wyatt AU - Michael Shtutman Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/03/31/591438.abstract N2 - HIV-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. ER -