Single-Cell Multi-Modal Differential Analysis of the Human Neo-Cortex in HIV Infection Reveals Similarities with Hallmarks of Alzheimer’s Disease

Cognitive impairment in people with HIV (PWH) remains prevalent despite viral suppression. To provide insights into the cellular mechanisms of pathogenesis, we carried out a multi-modal pan cell-type specific differential analysis of the frontal cortex of PWH. We show cell type-specific dysregulations of oxidative phosphorylation, glycolysis, ribosomes and translation, DNA damage, and neuroinflammation in PWH. Key genes and pathways identified showed a considerable overlap with transcriptional hallmarks of Alzheimer’s disease (AD) and involved AD vulnerable cell types, among others. We computed several differentially accessible chromatin sites in all major cell-types. Neuronal genes with perturbed chromatin accessibility regions were enriched in synaptic signaling genes supporting an epigenetic contribution to cognitive impairment in HIV. Convergent mechanisms of pathogenesis between HIV and AD support that broad therapeutic targets can be identified to ameliorate neurodegeneration and neuroinflammation in HIV and neurodegenerative conditions such as AD.