Transcriptional signature of induced neurons differentiates virologically suppressed people with HIV from people without HIV

Neurocognitive impairment is a prevalent comorbidity in virologically suppressed people living with HIV (PLWH), yet the underlying mechanisms remain elusive and treatments lacking. We explored use of participant-derived directly induced neurons (iNs) to model neuronal biology and injury in PLWH. iNs retain age- and disease-related donor features, providing unique opportunities to reveal important aspects of neurological disorders. We obtained primary dermal fibroblasts from 6 virologically suppressed PLWH and 7 matched people without HIV (PWOH). iNs were generated using transcription factors NGN2 and ASCL1 and validated by immunocytochemistry, single-cell RNA-Seq, and electrophysiological recordings. Transcriptomic aging analyses confirmed retention of donor age-related signatures. Bulk RNA-Seq identified 29 significantly differentially expressed genes between PLWH and PWOH iNs. Of these, 16 were downregulated and 13 upregulated in PLWH iNs. Protein-protein interaction network mapping indicated iNs from PLWH exhibited differences in extracellular matrix organization and synaptic transmission. IFI27 was upregulated in PLWH iNs, complementing independent postmortem studies demonstrating elevated IFI27 expression in PLWH-derived brain tissue. FOXL2NB-FOXL2-LINC01391 expression was reduced in PLWH iNs and negatively correlated with neurocognitive impairment. Thus, we identified an iN gene signature of HIV revealing mechanisms of neurocognitive impairment in PLWH.