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

For people with HIV, substance use disorders (SUDs) are a prominent neurological risk factor, and impacts of both on dopaminergic pathways are a potential point of deleterious convergence. Insight about cellular changes related to HIV and/or SUD is limited, but would be valuable for informing interventions. We explore cell-type-specific transcriptional alterations in chronic HIV and opioid/cocaine SUD in postmortem substantia nigra, performing single-nucleus RNA sequencing for 90 donors. Using abnormality-tolerant analysis, we identify changes in dopaminergic/GABAergic neurons and microglia, and functional gene groups with highly coordinated altered expression across donors. We find that HIV but not SUD is associated with reduced dopamine transporter transcription in dopaminergic neurons, whereas SUD involves increased excitability, impaired postsynaptic function, and reduced-frequency presynaptic release. We observe HIV/SUD synergies that emerge only with both conditions present. For controlled HIV, synergies may permit HIV viral replication and mediate cytotoxic dopaminergic neuron damage. In uncontrolled HIV, synergies include SUD-mediated impacts on GABAergic/dopaminergic neurons that promote dopaminergic disinhibition.

Data citation

Wilson, A.M., Jacobs, M.M., Lambert, T.Y. et al. Transcriptional impacts of substance use disorder and HIV on human ventral midbrain neurons and microglia. Nat Commun 16, 9123 (2025). https://doi.org/10.1038/s41467-025-64193-5

Funding agency

NIDA

Grant numbers

1U01DA053600

Access

open

License

Public data available under CC BY 4.0; controlled access data subject to data use certification