Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia

For people with HIV, substance use disorders are a prominent neurological risk factor, and the impacts of both on dopaminergic pathways may pose a deleterious convergence. Here, we profile, at single nucleus resolution, substantia nigra transcriptomes of 90 postmortem donors in the context of chronic HIV and opioid/cocaine use disorders, including 67 prospectively characterized people with HIV. We report altered microglial expression for hundreds of pro- and anti-inflammatory regulators attributable to HIV, and separately, to opioid/cocaine disorders. Stepwise, progressive microglial dysregulation coupled to altered dopaminergic/GABAergic signaling is associated with substance/HIV dual diagnosis, and further with lack of viral suppression in blood. In suppressed donors, opioid/cocaine comorbidity is associated with microglial transcriptional changes permissive for HIV infection. Finally, HIV-related downregulation of monoamine reuptake transporters emerges specifically in dopaminergic neurons regardless of substance use disorder status or viral load, as do transcriptional signatures consistent with selective vulnerability of dopamine neurons.