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 (T_RM) cells. Salivary 16S rRNA sequencing revealed elevated levels of <i>Fusobacteria,</i> negatively correlating with the levels of CD8⁺ T_RM-like cells in PLWH. <i>In vitro</i> experiments showed that <i>Fusobacterium nucleatum</i> (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 T_RM-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.