A telomere-lipid-immunity axis linking viral integration to autoimmune disease risk.

Autoimmune diseases rise steeply with biological aging, reflecting progressive failure of immune regulation. Inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) represents a unique lifelong viral exposure in which the viral genome is embedded within host telomeres, potentially altering leukocyte telomere length (LTL), a core biomarker of immune aging. Circulating metabolites may further modify these viral-telomeric interactions. We analyzed 156,927 UK Biobank participants free of autoimmune disease at baseline. Baseline iciHHV-6 carrier status, LTL, and plasma metabolomic profiles were related to incident autoimmune disease during follow-up. Mediation and interaction models were used to test whether LTL and various metabolomic pathways mediated or modified viral effects. Over follow-up, 7.8% of participants developed autoimmune disease and 1.3% were iciHHV-6 carriers. iciHHV-6 was not directly associated with autoimmune disease despite higher baseline comorbidity. Longer LTL was independently protective overall, especially for rheumatoid arthritis, although it was positively associated with multiple sclerosis. iciHHV-6 carriers had longer LTL, yielding a small but significant indirect protective effect on autoimmune risk. LTL also modified viral effects, with stronger protection among iciHHV-6-positive individuals, suggesting telomere length buffers adverse viral-immune interactions. Metabolomic analyses showed that triglyceride-rich lipoproteins and proinflammatory lipids were associated with shorter LTL and higher autoimmune risk, whereas omega-3 fatty acids, albumin, and HDL phospholipids were protective. Lipidomic pathways mediated a substantial portion of the LTL-autoimmune association and modified viral effects. These findings identify a telomere-lipid-immunity axis linking lifelong viral integration, metabolic aging, and autoimmune susceptibility, highlighting biological aging pathways as targets for autoimmune disease prevention.