A Switch from Glial to Neuronal Gene Expression Alterations in the Spinal Cord of SIV-infected Macaques on Antiretroviral Therapy.

Abstract

Despite antiretroviral therapy (ART), HIV-associated peripheral neuropathy remains one of the most prevalent neurologic manifestations of HIV infection. The spinal cord is an essential component of sensory pathways, but spinal cord sampling and evaluation in people with HIV has been very limited, especially in those on ART. The SIV/macaque model allows for assessment of the spinal cord at key time points throughout infection with and without ART. In this study, RNA was isolated from the spinal cord of uninfected, SIV+, and SIV + ART animals to track alterations in gene expression using global RNA-seq. Next, the SeqSeek platform was used to map changes in gene expression to specific cell types. Pathway analysis of differentially expressed genes demonstrated that highly upregulated genes in SIV-infected spinal cord aligned with interferon and viral response pathways. Additionally, this upregulated gene set significantly overlapped with those expressed in myeloid-derived cells including microglia. Downregulated genes were involved in cholesterol and collagen biosynthesis, and TGF-b regulation of extracellular matrix. In contrast, enriched pathways identified in SIV + ART animals included neurotransmitter receptors and post synaptic signaling regulators, and transmission across chemical synapses. SeqSeek analysis showed that upregulated genes were primarily expressed by neurons rather than glia. These findings indicate that pathways activated in the spinal cord of SIV + ART macaques are predominantly involved in neuronal signaling rather than proinflammatory pathways. This study provides the basis for further evaluation of mechanisms of SIV infection + ART within the spinal cord with a focus on therapeutic interventions to maintain synaptodendritic homeostasis.