Background
Central nervous system (CNS) dysfunction is a recognized complication in some people with HIV (PWH). As part of SCORCH (a large-scale, consortium-wide effort examining transcriptional and epigenetic alterations in the brains of PWH), we aim to identify key cell populations and pathways affected by HIV that may be targeted in therapies for HIV-associated CNS dysfunction in insular cortex (INS), prefrontal cortex (PFC), and ventral striatum (VST).
Methods
Nuclei were isolated from frozen post-mortem tissue from INS, PFC, and VST of 20 PWH and 13 donors without HIV (PWoH). We profiled 88 transcriptomes and 86 chromatin accessibility profiles of samples that passed quality control using 10x Genomics Single Cell Multiome ATAC+Gene Expression. Reference atlases were used to identify major cell types (Fig. A). We performed individual-level pseudobulk differential expression (DE) analysis between PWH and PWoH within cell types and regions using EdgeR. ATAC-seq data were processed using Signac for all cell types.
Results
PWH and PWoH donors were similar in age (median: 47 vs. 43 years) and gender (20% vs. 23% female). In total, we analyzed transcriptomes of 384,858 cells from PWH and 289,135 cells from PWoH. We identified granular neuronal and glial populations in both groups. Cross-regional DE analysis revealed significant changes in glial populations including oligodendrocytes (Oligo), astrocytes (Astro), and microglia (Micro) in all regions. In PWH Astro, we observed upregulation of complement activation genes (CFI,C4A,C1RL,C1R,C4B) indicative of reactive Astro. Relative to PWoH, there was an increase in the relative abundance of Astro in all three brain regions in PWH, but only the INS was significantly different. SERPINA3, a gene linked to poor prognosis in many neurological diseases, was upregulated in PWH Astro transcriptionally and epigenetically (Fig. B). Micro in PWH exhibited signatures of inflammatory responses and activation. Downregulated genes in PWH Astro, Micro, and Oligo were enriched in synaptic signaling and organization pathways, suggesting functional dysregulation of glial cells.
Conclusions
We observed substantial transcriptional and epigenetic alterations in multiple glial cell types, revealing broader glial dysfunction in PWH. The epigenetic nature of these changes helps to elucidate disease etiology and suggests potential targets for therapeutics to suppress these dysfunctional and activated glial cells.