Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV.
Shanmuga S MahalingamSangeetha JayaramanN BhaskaranE SchneiderF FaddoulA Paes da SilvaM M LedermanR AsaadK Adkins-TravisL P ShriverP PandiyanPublished in: Nature communications (2023)
Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid infection model revealed that HIV infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of caspase-1, IL-1β, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (T regDys )/T helper 17 (Th17) cell ratios. Blockade of caspase-1 and polyamine synthesis intermediates reversed the T regDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 infection. Lastly, oral mucosal T regDys /Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and T reg dysfunction.
Keyphrases
- antiretroviral therapy
- hiv infected
- hiv positive
- human immunodeficiency virus
- hiv aids
- hepatitis c virus
- hiv testing
- end stage renal disease
- newly diagnosed
- ejection fraction
- men who have sex with men
- chronic kidney disease
- endothelial cells
- single cell
- prognostic factors
- cell death
- oxidative stress
- regulatory t cells
- gene expression
- poor prognosis
- south africa
- metabolic syndrome
- signaling pathway
- immune response
- induced apoptosis
- genome wide
- pluripotent stem cells