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Background <p>Emerging evidence implicates the envelope protein of human endogenous retrovirus type W (pHERV-W ENV) in the pathogenesis of multiple sclerosis (MS); however, its clinical utility as a biomarker remains incompletely defined. In this study, we demonstrate that pHERV-W ENV is enriched on serum-derived exosomes in patients with relapsing-remitting MS (RRMS), where it reflects both current disease activity and future risk.</p> Methods <p>Exosomal pHERV-W ENV levels were profiled across three cohorts: (1) a cross-sectional cohort including healthy controls, stable MS patients, and patients with active disease; (2) a longitudinal RRMS cohort with samples collected before, during, and after episodes of disease activity; and (3) a retrospective longitudinal cohort of newly diagnosed RRMS patients with three years of follow-up.</p> Results <p>We observed an increase in exosomal pHERV-W ENV expression during active disease, followed by a decline at follow-up. Levels of pHERV-W ENV expression during active disease positively correlated with Epstein-Barr virus (EBV)-derived latent membrane protein 2&#xa0;A (LMP2A) expression, supporting an association between endogenous retroviral expression and EBV activity. Flow cytometric profiling of immune cell subsets identified monocytes and B cells as the predominant sources of circulating pHERV-W ENV. Longitudinal profiling further revealed coordinated immune and vascular activation during active disease, including a significant positive correlation between exosomal pHERV-W ENV and the costimulatory molecule CD40. Notably, high baseline levels of exosomal pHERV-W ENV were associated with greater total disease activity events, defined as the sum of clinical relapses and MRI activity (new/enlarging T2 or gadolinium-enhancing (Gd+) lesions) over three years, as well as with accelerated loss of “No Evidence of Disease Activity” (NEDA) status over time.</p> Conclusion <p>These findings suggest that exosomal pHERV-W ENV expression may serve as a dynamic, non-invasive biomarker of disease activity with prognostic value in MS.</p>

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Exosomal pHERV-W ENV as a dynamic biomarker for relapse prediction and prognosis in multiple sclerosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月21日

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  • Esber S. Saba,
  • May F. Mrad,
  • Layane Nakib,
  • Vera Dermesrobian,
  • Joseph Abboud,
  • Samia J. Khoury

摘要

Background

Emerging evidence implicates the envelope protein of human endogenous retrovirus type W (pHERV-W ENV) in the pathogenesis of multiple sclerosis (MS); however, its clinical utility as a biomarker remains incompletely defined. In this study, we demonstrate that pHERV-W ENV is enriched on serum-derived exosomes in patients with relapsing-remitting MS (RRMS), where it reflects both current disease activity and future risk.

Methods

Exosomal pHERV-W ENV levels were profiled across three cohorts: (1) a cross-sectional cohort including healthy controls, stable MS patients, and patients with active disease; (2) a longitudinal RRMS cohort with samples collected before, during, and after episodes of disease activity; and (3) a retrospective longitudinal cohort of newly diagnosed RRMS patients with three years of follow-up.

Results

We observed an increase in exosomal pHERV-W ENV expression during active disease, followed by a decline at follow-up. Levels of pHERV-W ENV expression during active disease positively correlated with Epstein-Barr virus (EBV)-derived latent membrane protein 2 A (LMP2A) expression, supporting an association between endogenous retroviral expression and EBV activity. Flow cytometric profiling of immune cell subsets identified monocytes and B cells as the predominant sources of circulating pHERV-W ENV. Longitudinal profiling further revealed coordinated immune and vascular activation during active disease, including a significant positive correlation between exosomal pHERV-W ENV and the costimulatory molecule CD40. Notably, high baseline levels of exosomal pHERV-W ENV were associated with greater total disease activity events, defined as the sum of clinical relapses and MRI activity (new/enlarging T2 or gadolinium-enhancing (Gd+) lesions) over three years, as well as with accelerated loss of “No Evidence of Disease Activity” (NEDA) status over time.

Conclusion

These findings suggest that exosomal pHERV-W ENV expression may serve as a dynamic, non-invasive biomarker of disease activity with prognostic value in MS.