EcoHIV Treated Primary Microglia Exhibit a Highly Specialized and Sex-Dependent Transcriptional State

Abstract

The pathogenesis of HIV-1-associated neurocognitive disorders (HAND) is partly driven by microglial dysregulation. Indeed, HIV-1-induced microglial dyshomeostasis is characterized by a sustained pro-inflammatory state and exacerbated microglia proliferation. Herein, in vitro studies were conducted in primary microglia to elucidate the transcriptomic alterations underlying EcoHIV induced microglia hyperproliferation. Consistent with, and expanding upon, prior studies, treatment with EcoHIV exacerbated microglia proliferation evidenced by the upregulation of Pcna and Mki67. With regards to microglial receptors and adapter proteins, the transcriptomic expression of Trem2 and Dap12 was suppressed and increased, respectively, in microglia treated with EcoHIV. Crucially, dysregulation of the Trem2/Dap12 signaling complex explained 51.4% of the variance in microglial proliferation in EcoHIV treated microglia. A preliminary investigation of the Trem2-mediated microglial survival and immunoregulation pathway affords additional support for a unique EcoHIV-induced transcriptomic profile. Specifically, independent of biological sex, EcoHIV treatment upregulated Syk and downregulated Ctnnb1 mRNA expression. Notably, biological sex regulates precisely how EcoHIV treated microglia respond to the suppression of Trem2 and compensatory hyperproliferative state. Collectively, primary microglia treated with EcoHIV exhibit a highly specialized and sex-dependent transcriptional state. Enhancing our understanding of how HIV-1 alters microglial homeostasis is crucial for the identification of novel therapeutic targets for HAND.