Small molecule ONC201 inhibits HIV-1 replication in macrophages via FOXO3a and TRAIL

Runze Zhao, Yuju Li, Santhi Gorantla, Larisa Y Poluektova, Hai Lin, Fengtong Gao, Hongyun Wang, Jeffrey Zhao, Jialin C Zheng, Yunlong Huang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)134-145
Number of pages12
JournalAntiviral Research
Volume168
DOIs
StatePublished - Aug 1 2019

Fingerprint

HIV-1
Macrophages
Brain
Blood-Brain Barrier
TIC10 compound
Viral RNA
Basal Ganglia
Intraperitoneal Injections
Small Interfering RNA
HIV Infections
Transcription Factors
Clinical Trials
Cytokines
Injections

Keywords

  • FOXO3a
  • HIV-1
  • Macrophages
  • ONC201
  • Reservoir
  • TRAIL

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

Small molecule ONC201 inhibits HIV-1 replication in macrophages via FOXO3a and TRAIL. / Zhao, Runze; Li, Yuju; Gorantla, Santhi; Poluektova, Larisa Y; Lin, Hai; Gao, Fengtong; Wang, Hongyun; Zhao, Jeffrey; Zheng, Jialin C; Huang, Yunlong.

In: Antiviral Research, Vol. 168, 01.08.2019, p. 134-145.

Research output: Contribution to journalArticle

Zhao, Runze ; Li, Yuju ; Gorantla, Santhi ; Poluektova, Larisa Y ; Lin, Hai ; Gao, Fengtong ; Wang, Hongyun ; Zhao, Jeffrey ; Zheng, Jialin C ; Huang, Yunlong. / Small molecule ONC201 inhibits HIV-1 replication in macrophages via FOXO3a and TRAIL. In: Antiviral Research. 2019 ; Vol. 168. pp. 134-145.
@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",
year = "2019",
month = "8",
day = "1",
doi = "10.1016/j.antiviral.2019.05.015",
language = "English (US)",
volume = "168",
pages = "134--145",
journal = "Antiviral Research",
issn = "0166-3542",
publisher = "Elsevier",

}

TY - JOUR

T1 - Small molecule ONC201 inhibits HIV-1 replication in macrophages via FOXO3a and TRAIL

AU - Zhao, Runze

AU - Li, Yuju

AU - Gorantla, Santhi

AU - Poluektova, Larisa Y

AU - Lin, Hai

AU - Gao, Fengtong

AU - Wang, Hongyun

AU - Zhao, Jeffrey

AU - Zheng, Jialin C

AU - Huang, Yunlong

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

KW - FOXO3a

KW - HIV-1

KW - Macrophages

KW - ONC201

KW - Reservoir

KW - TRAIL

UR - http://www.scopus.com/inward/record.url?scp=85066754868&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066754868&partnerID=8YFLogxK

U2 - 10.1016/j.antiviral.2019.05.015

DO - 10.1016/j.antiviral.2019.05.015

M3 - Article

VL - 168

SP - 134

EP - 145

JO - Antiviral Research

JF - Antiviral Research

SN - 0166-3542

ER -