Modulation of Host BRD4 to Repress HIV Replication in Myeloid Cells: Major HIV Reservoirs in Central Nervous System
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Brain-resident microglia and myeloid cells (perivascular macrophages) are important HIV reservoirs in vivo, especially in central nerve system (CNS). Despite anti-retroviral 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 complimentary to ART to repressing residual HIV replication in CNS reservoirs are needed. Our group has recently identified a BRD4-selective small molecule modulator (ZL0580) that induces 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). Pre-treatment of microglia with ZL0580 renders them more refractory to latent HIV reactivation, indicating epigenetic reprogramming effect of ZL0580 on HIV LTR in microglia. We also demonstrated 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 MNase mapping identified that ZL0580 induces 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.