RNA-seq analysis of HIV-1 gp120 stimulated, p38a knockout and wild-type microglia isolated from mouse brain.

Purpose: The goals of this study is to compare transcriptome profiles of microglia from different mouse genotypes using RNA-seq analysis. HIV-associated neurocognitive disorders (HAND) occur in about 50% of infected individuals. Transgenic mice expressing the soluble HIV-1 envelope glycoprotein gp120 in astroglia (HIVgp120tg) display key neuropathological features of NeuroHIV patients (Toggas et al., 1994; Maung et al., 2014; Ojeda-Juarez et al., 2020). Here we show that microglial p38a MAPK plays a crucial role in neuronal injury triggered in vivo by the viral envelope glycoprotein. Cre-expression driven by the CX3CR1 promotor in HIVgp120tg mice carrying floxed alleles of p38a MAPK results in deletion of p38a in microglia and complete protection against neuronal injury and loss. RNA-seq analysis of microglia indicates that p38a deficiency leads to upregulation of neuroprotective and downregulation of neurotoxic factors. The expression patterns of genes associated with neurotransmission differ between brains protected from neuronal injury in the presence of transgenic gp120 and non-transgenic controls, suggesting a non-toxic modulation of neurons by the viral protein and microglial p38a deficiency. Overall design: Examination of microglia gene expression in 4 different genotypes [wild type (WT), gp120-transgenic (gp120), microglia specific p38a knockout (p38a KO) and microglia specific p38a knockout gp120-transgenic (gp120 p38a KO)]. 3 Males and 3 Females samples were analyzed in each genotype.