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

Philipp N. Ostermann,¹ Youjun Wu,² Scott Bowler,¹ Samuel Martínez-Meza,¹ Mohammad A. Siddiqui,⁴ David H. Meyer,⁵ Alberto Herrera,¹ Brandon A. Sealy,⁶ Mega Sidharta,² Kiran Ramnarine,² Leslie Ann St. Bernard,¹ Desiree Byrd,⁷ R. Jones,¹ Masahiro Yamashita,⁴ Douglas F. Nixon,¹ Lishomwa C. Ndhlovu,¹ Ting Zhou,⁸ and Teresa H. Evering¹

Published December 1, 2025 - More info

Neurocognitive impairment is a prevalent co-morbidity 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 six virologically suppressed PLWH (range: 27-64 years, median: 53; 83% Male) and seven matched people without HIV (PWOH) (range: 27-66, median: 55; 71% Male). iNs were generated using transcription factors NGN2 and ASCL1, and validated by immunocytochemistry, single-cell-RNAseq, and electrophysiological recordings. Transcriptomic aging analyses confirmed retention of donor age-related signatures. Bulk-RNAseq 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 indicates iNs from PLWH exhibit differences in extracellular matrix organization and synaptic transmission. IFI27 was upregulated in PLWH iNs, complementing independent post-mortem 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.

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