@article{749031de6db34d4997d6a98ee60c98fd,
title = "Small molecule ONC201 inhibits HIV-1 replication in macrophages via FOXO3a and TRAIL",
abstract = "Despite the success of antiretroviral therapy (ART), eradication of HIV-1 from brain reservoirs remains elusive. HIV-1 brain reservoirs include perivascular macrophages that are behind the blood-brain barrier and difficult to access by ART. Macrophages express transcription factor FOXO3a and the TNF superfamily cytokine TRAIL, which are known to target HIV-1-infected macrophages for viral inhibition. ONC201 is a novel and potent FOXO3a activator capable of inducing TRAIL. It can cross the blood-brain barrier, and has shown antitumor effects in clinical trials. We hypothesized that activation of FOXO3a/TRAIL by ONC201 will inhibit HIV-1 replication in macrophages. Using primary human monocyte-derived macrophages, we demonstrated that ONC201 dose-dependently decreased replication levels of both HIV-1 laboratory strain and primary strains as determined by HIV-1 reverse transcriptase activity assay. Consistent with data on HIV-1 replication, ONC201 also reduced intracellular and extracellular p24, viral RNA, and integrated HIV-1 DNA in infected macrophages. Blocking TRAIL or knockdown of FOXO3a with siRNA reversed ONC201-mediated HIV-1 suppression, suggesting that ONC201 inhibits HIV-1 through FOXO3a and TRAIL. The anti-HIV-1 effect of ONC201 was further validated in vivo in NOD/scid-IL-2Rgcnull mice. After intracranial injection of HIV-1-infected macrophages into the basal ganglia, we treated the mice daily with ONC201 through intraperitoneal injection for six days. ONC201 significantly decreased p24 levels in both the macrophages and the brain tissues, suggesting that ONC201 suppresses HIV-1 in vivo. Therefore, ONC201 can be a promising drug candidate to combat persistent HIV-1 infection in the brain.",
keywords = "FOXO3a, HIV-1, Macrophages, ONC201, Reservoir, TRAIL",
author = "Runze Zhao and Yuju Li and Santhi Gorantla and Poluektova, {Larisa Y.} and Hai Lin and Fengtong Gao and Hongyun Wang and Jeffrey Zhao and Zheng, {Jialin C.} and Yunlong Huang",
note = "Funding Information: This work was supported in part by research grants by the National Institutes of Health : R01 NS097195 (JCZ), R24 OD018546 (LP, SG), R03 NS094071 (YH), 2P30MH062261-Developmental (YH), the State Key Program of the National Natural Science Foundation of China (# 81830037 to JCZ), the National Basic Research Program of China (973 Program Grant No. 2014CB965001 to JCZ), the Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (# 81329002 to JCZ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: This work was supported in part by research grants by the National Institutes of Health: R01 NS097195 (JCZ), R24 OD018546 (LP, SG), R03 NS094071 (YH), 2P30MH062261-Developmental (YH), the State Key Program of the National Natural Science Foundation of China (#81830037 to JCZ), the National Basic Research Program of China (973 Program Grant No. 2014CB965001 to JCZ), the Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (#81329002 to JCZ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: HIV-1 infected U937 Cells (U1) from Dr. Thomas Folks. We kindly thank Li Wu, Na Ly, and Myhanh Che for providing technical support; Justin Peer and Lenal Bottoms for proofreading the manuscript; Julie Ditter, Johna Belling, and Robin Taylor for providing outstanding administrative and secretarial support. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = aug,
doi = "10.1016/j.antiviral.2019.05.015",
language = "English (US)",
volume = "168",
pages = "134--145",
journal = "Antiviral Research",
issn = "0166-3542",
publisher = "Elsevier",
}