@article {Aksenova591438, author = {Marina Aksenova and Justin Sybrandt and Biyun Cui and Vitali Sikirzhytski and Hao Ji and Diana Odhiambo and Mathew D. Lucius and Jill R. Turner and Eugenia Broude and Edsel Pe{\~n}a and Sofia Lizzaraga and Jun Zhu and Ilya Safro and Michael D Wyatt and Michael Shtutman}, title = {Inhibition of the Dead Box RNA Helicase 3 prevents HIV-1 Tat and cocaine-induced neurotoxicity by targeting microglia activation}, elocation-id = {591438}, year = {2019}, doi = {10.1101/591438}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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.}, URL = {https://www.biorxiv.org/content/early/2019/03/31/591438}, eprint = {https://www.biorxiv.org/content/early/2019/03/31/591438.full.pdf}, journal = {bioRxiv} }