Inhibition of the DDX3 prevents HIV-1 Tat and cocaine-induced neurotoxicity by targeting microglia activation

November 19, 2019

Journal of Neuroimmune Pharmacology (Accepted, Publication Pending)

  • Marina Aksenova
  • Justin Sybrandt
  • Biyun Cui
  • Vitali Sikirzhytski
  • Hao Ji
  • Diana Odhiambo
  • Mathew Lucius
  • Jill R Turner
  • Eugenia Broude
  • Edsel Pena
  • Sofia Lizzaraga
  • Jun Zhu
  • Ilya Safro
  • Michael D Wyatt
  • Michael Shtutman

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