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<p>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.&#xa0;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.&#xa0;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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • May A. Beydoun,
  • Minkyo Song,
  • Choa Yun,
  • Hind A. Beydoun,
  • Nigus G. Asefa,
  • Jordan Weiss,
  • Nicole Noren Hooten,
  • Michele K. Evans,
  • Alan B. Zonderman

摘要

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.

Graphical Abstract