Dysbiosis modulates CD8+ tissue-resident memory cells through a mechanism requiring polyamine metabolism during HIV infection.

Polyamines play crucial roles in modulating T lymphocyte functions. Here, we demonstrate that the oral mucosa of people living with HIV (PLWH), characterized by active polyamine metabolic pathways, exhibits significantly diminished IFN-γ expression and reduced abundance of CD8+ tissue-resident memory (TRM) cells. Salivary 16S rRNA sequencing revealed elevated levels of Fusobacteria, negatively correlating with the levels of CD8+ TRM-like cells in PLWH. In vitro experiments showed that Fusobacterium nucleatum (FN) produced putrescine, which is known to be enriched in PLWH mucosa. Polyamines, HIV infection, and FN led to EIF-5A hypusination, diminished IFN-γ expression in CD8+ T cells, which impaired the proliferation of TRM-like cells in tonsil organoid cells. The inhibition of polyamine synthesis and EIF-5A hypusination restored IFN-γ expression and TRM-like cells. Collectively, these results highlight an essential role of polyamines in the critical interplay between oral resident microbiota, immunometabolic regulation, and immune competence during chronic viral infections.