Epigenetic suppression of HIV in myeloid cells by the BRD4-selective small molecule modulator ZL0580

Edrous Alamer, Chaojie Zhong, Zhiqing Liu, Qingli Niu, Fuquan Long, Lulu Guo, Benjamin B. Gelman, Lynn Soong, Jia Zhou, Haitao Hu

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Brain-resident microglia and myeloid cells (perivascular macrophages) are important HIV reservoirs in vivo, especially in the central nervous system (CNS). Despite antiretroviral therapy (ART), low-level persistent HIV replication in these reservoirs remains detectable, which contributes to neuroinflammation and neurological disorders in HIV-infected patients. New approaches complementary to ART to repress residual HIV replication in CNS reservoirs are needed. Our group has recently identified a BRD4-selective small molecule modulator (ZL0580) that induces the epigenetic suppression of HIV. Here, we examined the effects of this compound on HIV in human myeloid cells. We found that ZL0580 induces potent and durable suppression of both induced and basal HIV transcription in microglial cells (HC69) and monocytic cell lines (U1 and OM10.1). Pretreatment of microglia with ZL0580 renders them more refractory to latent HIV reactivation, indicating an epigenetic reprogramming effect of ZL0580 on HIV long terminal repeat (LTR) in microglia. We also demonstrate that ZL0580 induces repressive effect on HIV in human primary monocyte-derived macrophages (MDMs) by promoting HIV suppression during ART treatment. Mechanistically, ZL0580 inhibits Tat transactivation in microglia by disrupting binding of Tat to CDK9, a process key to HIV transcription elongation. High-resolution micrococcal nuclease mapping showed that ZL0580 induces a repressive chromatin structure at the HIV LTR. Taken together, our data suggest that ZL0580 represents a potential approach that could be used in combination with ART to suppress residual HIV replication and/or latent HIV reactivation in CNS reservoirs, thereby reducing HIV-associated neuroinflammation.

Original languageEnglish (US)
Article numbere01880-19
JournalJournal of virology
Volume94
Issue number11
DOIs
StatePublished - Jun 1 2020

Keywords

  • BRD4
  • BRD4 modulator
  • CNS
  • Epigenetic suppression
  • HIV/AIDS
  • Microglia
  • Myeloid cells

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Fingerprint Dive into the research topics of 'Epigenetic suppression of HIV in myeloid cells by the BRD4-selective small molecule modulator ZL0580'. Together they form a unique fingerprint.

  • Cite this