A critical in vivo role for microglial p38α MAPK in HIV-1 associated inflammatory brain injury.

People with HIV (PWH) develop neurocognitive impairment despite control of viral infection. Key pathological features of NeuroHIV patients, including activated microglia, neuronal damage and behavioral impairment, are present in transgenic mice expressing HIV-1 envelope glycoprotein gp120 in their brain (HIVgp120tg). Here we show that microglial mitogen-activated protein kinase p38α plays a crucial in vivo role in neuronal injury triggered by viral gp120. Cre-expression driven by the Cx3cr1 promotor in HIVgp120tg mice with floxed p38α alleles results in deletion of microglial p38α and protection from neuronal injury and behavioral impairment. Moreover, the expression patterns of neurotransmission-related genes differ between gp120-transgenic brains protected from neuronal injury and non-transgenic controls, suggesting that microglial p38α deficiency permits a non-toxic modulation of neurons in the presence of the viral protein. Bulk RNA-seq analysis of murine microglia and follow-up in human microglial cells in which p38α has been knocked out using CRISPR/Cas9 technology using qRT-PCR reveals that deficiency of the kinase leads to a distinct gene expression pattern of reduced inflammatory but preserved anti-viral responses.