The gene in question is STING1, also known as TMEM173, which encodes the stimulator of interferon genes, or STING, protein. STING sits at the heart of the cGAS-STING pathway, a cytosolic DNA-sensing system that acts as a cellular alarm. When double-stranded DNA appears in the cytoplasm, whether from HIV reverse transcription intermediates, from damaged mitochondria, or from the mislocalized host DNA that accumulates with genomic instability and telomere shortening, the enzyme cyclic GMP-AMP synthase, or cGAS, converts it into the second messenger 2’3′-cyclic GMP-AMP. cGAMP then activates STING, an endoplasmic reticulum-localized transmembrane protein, which traffics through the ER-Golgi intermediate compartment to the Golgi apparatus. There it triggers phosphorylation of TANK-binding kinase 1 and IκB kinase, which in turn activate interferon regulatory factor 3 and nuclear factor-κB, driving a robust induction of type I interferons and interferon-stimulated genes. Beyond antiviral defense, this pathway modulates autophagy, apoptosis, cellular senescence, and metabolism, and it has been implicated in cardiovascular disease, cancer, neurodegeneration, and the aging process itself.

Crucially, STING1/TMEM173 is genetically heterogeneous. A haplotype called HAQ, composed of three missense variants, R71H, G230A, and R293Q, is carried by roughly twenty percent of the human population, with frequencies varying by ethnicity. This haplotype is hypomorphic, meaning it partially impairs function: homozygous HAQ/HAQ individuals show markedly reduced STING protein expression and minimal responsiveness to cyclic dinucleotides, producing far less interferon-beta than wild-type carriers. A second common polymorphism, R232H, impairs sensing of viral and bacterial cyclic dinucleotides, reducing phosphorylation of TBK1 and IRF3, diminishing interferon-alpha transcription, and impairing monocyte function. These variants cumulatively dampen STING-mediated innate immune activation, and prior work has linked them to protection in STING-driven autoinflammatory syndromes such as COPA syndrome, as well as to a decreased risk of aging-associated diseases in population studies.

The rationale for examining these variants in HIV comes from earlier evidence. In a study of Danish long-term non-progressors, the HAQ/HAQ or AQ/AQ genotype was found in about eighteen percent of participants, enriched among these slow progressors but absent in non-controllers receiving therapy. Functional assays showed that carriers displayed reduced innate responses to HIV- and DNA-derived stimuli and lower constitutive type I interferon activation, suggesting that attenuated STING signaling may slow disease progression by limiting the chronic interferon-driven immune activation that erodes T cell homeostasis. Yet beyond that single cohort, virtually nothing was known about how these variants affect systemic inflammation, comorbidity burden, or cognitive and physical outcomes in aging people living with HIV, a rapidly expanding segment of the global HIV population.

To address this gap, the Brescia team conducted a cross-sectional, single-center pilot study of sixty people living with HIV, all over fifty years old, diagnosed at least a decade earlier, and stably maintained on antiretroviral therapy. Participants were recruited between November 2019 and February 2020 at the outpatient HIV clinic of the Spedali Civili Hospital in Brescia, Italy. Genomic DNA was extracted from peripheral blood and the relevant regions of STING1/TMEM173 were amplified by PCR and sequenced directly by the Sanger method, allowing classification of carriers of the R71H, G230A, R293Q, and R232H polymorphisms. The researchers then compared genotype groups across a battery of outcomes: viro-immunological parameters, comorbidities defined by standardized clinical criteria, cognitive performance assessed with the Mini-Mental State Examination and the Clock Drawing Test, and physical function measured with the Short Physical Performance Battery, with appropriate statistical controls for age, education, and duration of HIV infection.

The cohort itself reflected the burden of long-term infection. Forty-five of the sixty participants were male, the median age was 69.5 years, and the median time on antiretroviral therapy was eighteen years. All patients had undetectable plasma HIV RNA, with a median CD4-positive T cell count of 546 cells per cubic millimeter. Comorbidities were common: hypertriglyceridemia affected 38.3 percent, hypercholesterolemia 35 percent, liver disease 33.3 percent, hypertension 31.7 percent, and cardiovascular disease 26.7 percent, and 58.3 percent of patients carried at least two comorbidities. Genotyping revealed that 21 participants, or 35 percent, carried the HAQ haplotype or its partial forms, 14 carried the H232 allele, and 28 were wild-type at all four positions.

The headline finding concerned metabolism. Carriers of the HAQ haplotype, or of any of its three linked polymorphisms, showed a significantly lower prevalence of dyslipidemia compared with wild-type patients, and this difference persisted even when the analysis excluded individuals who also carried the H232 variant and even after adjusting for the duration of HIV infection. Carriers of these hypomorphic alleles also tended to have a lower mean number of comorbidities overall. The authors interpret this as a possible consequence of a lower systemic inflammatory tone, mediated by diminished type I interferon signaling and reduced inflamm-aging. The interpretation gains plausibility from experimental literature showing that STING signaling is tightly linked to lipid homeostasis: STING deficiency in mice protects against adipose tissue inflammation, elevated circulating lipids, insulin resistance, and hepatic steatosis, while STING has been shown to inhibit the fatty acid desaturase FADS2, an enzyme central to polyunsaturated fatty acid metabolism. In pathological settings of chronic STING activation, such as persistent HIV infection, this modulation may contribute to metabolic comorbidities like dyslipidemia, so partially blunted STING function could plausibly be protective.

The immune findings were equally striking, though in the opposite direction. Carriers of the H232 variant showed significantly higher CD4-positive T cell counts than wild-type individuals or all other patients combined, despite similar age and disease duration, suggesting that partial impairment of STING function may support CD4 T cell homeostasis during immune recovery. The most dramatic illustration came from two rare individuals. The cohort’s single HAQ/HAQ homozygote, a 77-year-old man diagnosed 21 years earlier after presenting with disseminated cytomegalovirus infection, esophageal candidiasis, and non-tuberculous mycobacterial infection, now maintains only partial but sufficient viro-immunological control with 477 CD4 cells per cubic millimeter and no severe clinical outcomes. Even more remarkable was the sole H232/H232 homozygote, an 85-year-old woman with a 34-year history of HIV infection who has never started antiretroviral therapy, yet has maintained undetectable viremia, high CD4 counts of 656 cells per cubic millimeter, a normal CD4-to-CD8 ratio of 1.03, normal cognition, and normal motor performance throughout decades of follow-up. She may represent a further example of a STING variant contributing to spontaneous viral control in a long-term non-progressor.

Not every question was resolved. No significant differences emerged between genotype groups in cognitive performance on the MMSE and Clock Drawing Test or in physical performance on the SPPB, possibly because the small sample lacked power to detect subtle effects, or because the screening instruments used are insensitive to the frontal and executive deficits characteristic of HIV-associated neurocognitive impairment. The authors are candid about the limitations: the sample was small and retrospective, homozygotes were vanishingly rare, data on specific antiretroviral drug classes were unavailable as a potential confounder for dyslipidemia, and no direct measurements of interferon or cytokines were made, so the mechanistic link between genotype and clinical outcome remains inferred from prior in vitro and animal work rather than demonstrated in the cohort itself. The findings must therefore be considered strictly exploratory.

Even so, the study opens a genuinely new line of inquiry into why aging people living with HIV diverge so widely in their comorbidity trajectories. If common, partially disabling variants in a single innate immune sensor can shift the balance between chronic inflammation and metabolic or immunological resilience, then the cGAS-STING axis may be a determinant of healthspan in long-treated HIV infection, and perhaps a target for intervention. The authors call for larger, prospective studies integrating inflammatory biomarkers and transcriptomic profiling to confirm whether hypomorphic STING1/TMEM173 variants truly predict immuno-metabolic resilience, and to clarify how this ancient DNA-sensing pathway, so essential for antiviral defense, can become both a driver of aging-related disease and, when quietly weakened, an unexpected ally of longevity.

Subject of Research: Hypomorphic STING1/TMEM173 gene variants and immuno-metabolic outcomes in aging people living with HIV

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

Article References: Zanella, I., Fornari, C., Cesanelli, F., Tiecco, G., Zacchi, E., Bouros, C., Codenotti, S., Ferraro, R. M., Fanzani, A., Giliani, S., & Quiros-Roldan, E. (2026). Hypomorphic STING1/TMEM173 variants may support immuno-metabolic resilience in aging people living with HIV. GeroScience. https://doi.org/10.1007/s11357-026-02561-9

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02561-9

Keywords: STING1, TMEM173, cGAS-STING pathway, HIV, aging, immunosenescence, dyslipidemia, CD4 T cells, polymorphism, inflammaging, long-term non-progressors, antiretroviral therapy