TY - JOUR
T1 - Inhibition of the Dead Box RNA Helicase 3 Prevents HIV-1 Tat and Cocaine-Induced Neurotoxicity by Targeting Microglia Activation
AU - Aksenova, Marina
AU - Sybrandt, Justin
AU - Cui, Biyun
AU - Sikirzhytski, Vitali
AU - Ji, Hao
AU - Odhiambo, Diana
AU - Lucius, Matthew D.
AU - Turner, Jill R.
AU - Broude, Eugenia
AU - Peña, Edsel
AU - Lizarraga, Sofia
AU - Zhu, Jun
AU - Safro, Ilya
AU - Wyatt, Michael D.
AU - Shtutman, Michael
N1 - Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - HIV-1 Associated Neurocognitive Disorder (HAND) is a common and clinically detrimental complication of HIV infection. Viral proteins, including Tat, released from infected cells, cause neuronal toxicity. Substance abuse in HIV-infected patients greatly influences the severity of neuronal damage. To repurpose small molecule inhibitors for anti-HAND therapy, we employed MOLIERE, an AI-based literature mining system that we developed. All human genes were analyzed and prioritized by MOLIERE to find previously unknown targets connected to HAND. From the identified high priority genes, we narrowed the list to those with known small molecule ligands developed for other applications and lacking systemic toxicity in animal models. To validate the AI-based process, the selective small molecule inhibitor of DDX3 helicase activity, RK-33, was chosen and tested for neuroprotective activity. The compound, previously developed for cancer treatment, was tested for the prevention of combined neurotoxicity of HIV Tat and cocaine. Rodent cortical cultures were treated with 6 or 60 ng/ml of HIV Tat and 10 or 25 μM of cocaine, which caused substantial toxicity. RK-33 at doses as low as 1 μM greatly reduced the neurotoxicity of Tat and cocaine. Transcriptome analysis showed that most Tat-activated transcripts are microglia-specific genes and that RK-33 blocks their activation. Treatment with RK-33 inhibits the Tat and cocaine-dependent increase in the number and size of microglia and the proinflammatory cytokines IL-6, TNF-α, MCP-1/CCL2, MIP-2, IL-1α and IL-1β. These findings reveal that inhibition of DDX3 may have the potential to treat not only HAND but other neurodegenerative diseases. [Figure not available: see fulltext.].
AB - HIV-1 Associated Neurocognitive Disorder (HAND) is a common and clinically detrimental complication of HIV infection. Viral proteins, including Tat, released from infected cells, cause neuronal toxicity. Substance abuse in HIV-infected patients greatly influences the severity of neuronal damage. To repurpose small molecule inhibitors for anti-HAND therapy, we employed MOLIERE, an AI-based literature mining system that we developed. All human genes were analyzed and prioritized by MOLIERE to find previously unknown targets connected to HAND. From the identified high priority genes, we narrowed the list to those with known small molecule ligands developed for other applications and lacking systemic toxicity in animal models. To validate the AI-based process, the selective small molecule inhibitor of DDX3 helicase activity, RK-33, was chosen and tested for neuroprotective activity. The compound, previously developed for cancer treatment, was tested for the prevention of combined neurotoxicity of HIV Tat and cocaine. Rodent cortical cultures were treated with 6 or 60 ng/ml of HIV Tat and 10 or 25 μM of cocaine, which caused substantial toxicity. RK-33 at doses as low as 1 μM greatly reduced the neurotoxicity of Tat and cocaine. Transcriptome analysis showed that most Tat-activated transcripts are microglia-specific genes and that RK-33 blocks their activation. Treatment with RK-33 inhibits the Tat and cocaine-dependent increase in the number and size of microglia and the proinflammatory cytokines IL-6, TNF-α, MCP-1/CCL2, MIP-2, IL-1α and IL-1β. These findings reveal that inhibition of DDX3 may have the potential to treat not only HAND but other neurodegenerative diseases. [Figure not available: see fulltext.].
KW - Cocaine
KW - DDX3
KW - Dead box RNA helicase
KW - HAND
KW - HIV
KW - Microglia
KW - Tat
UR - http://www.scopus.com/inward/record.url?scp=85076216549&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076216549&partnerID=8YFLogxK
U2 - 10.1007/s11481-019-09885-8
DO - 10.1007/s11481-019-09885-8
M3 - Article
C2 - 31802418
AN - SCOPUS:85076216549
SN - 1557-1890
VL - 15
SP - 209
EP - 223
JO - Journal of NeuroImmune Pharmacology
JF - Journal of NeuroImmune Pharmacology
IS - 2
ER -