Inhibition of the Dead Box RNA Helicase 3 Prevents HIV-1 Tat and Cocaine-Induced Neurotoxicity by Targeting Microglia Activation

• DOI: 10.1007/s11481-019-09885-8
• Publication Date: 2019-12-04T20:02:35Z
• Authors: Marina Aksenova; Justin Sybrandt; Biyun Cui; Vitali Sikirzhytski; Hao Ji; Diana Odhiambo; Matthew D. Lucius; Jill R. Turner; Eugenia Broude; Edsel Peña; Sofia Lizarraga; Jun Zhu; Ilya Safro; Michael D. Wyatt; Michael Shtutman
• Keywords: Male; AIDS Dementia Complex; Dose-Response Relationship, Drug; Imidazoles; Azepines; Rats; 3. Good health; DEAD-box RNA Helicases; Rats, Sprague-Dawley; Cocaine; Dopamine Uptake Inhibitors; Animals; Female; tat Gene Products, Human Immunodeficiency Virus; Microglia; Cells, Cultured

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.