Hypomorphic STING1/TMEM173 variants may support immuno-metabolic resilience in aging people living with HIV

Abstract Antiretroviral therapy (ART) has significantly increased life expectancy of people living with HIV (PLWH). Nonetheless, despite effective virological control, PLWH are faced with accelerated aging, characterized by higher prevalence of age-related comorbidities than the general population. Persistent inflammation and activation of innate immunity seem to drive this immunosenescent phenotype. The cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is increasingly recognized as a key player in the aging process and in age-related diseases, like cardiovascular and metabolic disorders, cancer, neurological diseases and cognitive decline. The human gene encoding for STING (STING1/TMEM173) exhibit significant heterogeneity, with some common single nucleotide polymorphisms (SNPs) variably affecting its immune functions (R232H and R71H, G230A, R293Q, frequently co-segregating as HAQ haplotype). This study aims to investigate the impact of those hypomorphic variants on immune control, comorbidities, and cognitive and functional outcomes in a cohort of 60 aged (> 50 years) chronic PLWH on stable ART. Patients were genotyped and differences in comorbidities, HIV-related clinical parameters, and cognitive and motor performances were assessed across genotype groups. Here we show that carriers of R71H, G230A and R293Q alleles were associated with a lower prevalence of dyslipidemia, while carriers of the R232H polymorphism show higher CD4⁺ T cell counts. Our results suggest that the common STING1/TMEM173 polymorphisms may influence immunological and clinical outcomes, modulating lipid metabolism and the dynamics of immune recovery in these people.