1. Academic Validation
  2. The Glucocorticoid Receptor Is a Critical Regulator of HIV Latency in Human Microglial Cells

The Glucocorticoid Receptor Is a Critical Regulator of HIV Latency in Human Microglial Cells

  • J Neuroimmune Pharmacol. 2019 Mar;14(1):94-109. doi: 10.1007/s11481-018-9798-1.
David Alvarez-Carbonell 1 Fengchun Ye 1 Nirmala Ramanath 1 Curtis Dobrowolski 1 Jonathan Karn 2
Affiliations

Affiliations

  • 1 Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • 2 Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, 44106, USA. [email protected].
Abstract

We have developed models of HIV latency using microglia derived from adult human patient brain cortex and transformed with the SV40 T large and hTERT antigens. Latent clones infected by HIV reporter viruses display high levels of spontaneous HIV reactivation in culture. BrainPhys, a medium highly representative of the CNS extracellular environment, containing low glucose and 1% FBS, reduced, but did not prevent, HIV reactivation. We hypothesized that spontaneous HIV reactivation in culture was due to the expression of pro-inflammatory genes, such as TNF-α, taking place in the absence of the natural inhibitory signals from astrocytes and neurons. Indeed, expression and secretion of TNF-α is strongly reduced in HIV-latently infected microglia compared to the subset of cells that have undergone spontaneous HIV reactivation. Whereas inhibitors of NF-κB or of macrophage activation only had a short-term silencing effect, addition of dexamethasone (DEXA), a Glucocorticoid Receptor (GR) agonist and mediator of anti-inflammation, silenced the HIV provirus in a long-term, and shRNA-mediated knock-down of GR activated HIV. DEXA also decreased secretion of a number of cytokines, including TNF-α. Chromatin immunoprecipitation analysis revealed that DEXA strongly increased GR occupancy at the HIV promoter, and reduced histone 3 acetylated levels. Moreover, TNF-α expression inhibitors in combination with DEXA induced further HIV silencing and increased the histone 3 lysine 27 tri-methylated epigenetic mark of repression at the HIV promoter region. We conclude that GR is a critical repressor of HIV transcription in microglia, and a novel potential pharmacological target to restrict HIV expression in the CNS.

Keywords

Dexamethasone; Glucocorticoid receptor; Glucocorticoids; HIV-associated neurocognitive disorders; HIV-induced neurocognitive disorders; Microglial activation; TNF-α.

Figures
Products