Polyamines and Epithelial Barrier Loss During HIV Infection

Despite effective antiretroviral therapy (ART), people with HIV (PWH) continue to experience chronic oral mucosal disease characterized by persistent T-cell inflammation, regulatory T cell (Treg) dysfunction, impaired CD8+ tissue resident cell (TRM) immunity and microbial dysbiosis. Emerging evidence implicates dysregulated polyamine metabolism and mucosal T-cell dysfunction as key mediators of these pathological processes. However, the effects of polyamines on the oral mucosal epithelium remain largely unexplored. The paradoxical dose-dependent effects of polyamines on oral epithelial barrier integrity are critically discussed, and a unified mechanistic model is proposed. This paper also highlights single-cell transcriptomic data from our laboratory that implicates epithelial cell barrier dysfunction in PWH and offers a perspective on how it may worsen persistent inflammation even after combined anti-retroviral treatment. This hypothesis reports current knowledge on how HIV-induced polyamine overload and Fusobacterium-derived putrescine could drive oral epithelial barrier disruption through interconnected mechanisms involving oxidative stress, α6β4 integrin–laminin-332 signaling, HIF-1α stabilization, tight junction disorganization, and innate immune dysregulation. Finally, we outline key future research directions, including therapeutic targeting of polyamine oxidation to restore oral mucosal homeostasis in PWH.