Population-scale sequencing resolves determinants of persistent EBV DNA, 2026, Nyeo et al

[Manuel]

A new immunology study provides solid evidence that the persistence of Epstein–Barr virus (EBV) is modulated by how HLA class II molecules present viral antigens to CD4⁺ T cells.
https://www.nature.com/articles/s41586-025-10020-2

The study shows that specific differences in antigen presentation may promote:

-prolonged immune stimulation
-viral antigen persistence
-sustained T cell activation
-chronic low-grade inflammation
-loss of immune tolerance
-generation of autoantibodies and autoreactive phenomena

This mechanism is highlighted as relevant for post-viral syndromes, persistent fatigue symptoms, autonomic dysfunction, and chronic inflammatory conditions in which EBV acts as a biological cofactor.

But most importantly, this pathogenic axis is NOT new to us.

We had already described this mechanism in our previous three studies
The processes emphasized in this new work are exactly the same as those proposed in our earlier publications:

EBV as an immunological origin of ME/CFS (Frontiers in Immunology, 2021)
We described that:
-EBV latency and reactivation can generate persistent antigenic stimulation
-this maintains abnormal immune activation
-and promotes loss of immune regulation and chronic systemic symptoms

We proposed that the inability to control EBV-infected cells is a key driver of pathophysiology in patients with HLA-II genetic susceptibility.
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.656797/full

EBV-induced acquired immunodeficiency in ME/CFS and long COVID
(Journal of Translational Medicine, 2023)
We showed that:
-ME/CFS and long COVID share an EBV reactivation/persistence axis
-leading to a state of chronic immune dysfunction
-with sustained inflammation, impaired antiviral surveillance, and multisystem symptoms, particularly in patients with ancestral HLA-II haplotypes.
https://link.springer.com/article/10.1186/s12967-023-04515-7

Ancestral HLA-II haplotypes and autoimmune diseases
(Frontiers in Immunology, 2025)
Here we linked the genetic component to other autoimmune diseases:
-DR2-DQ6, DR3-DQ2, DR4-DQ8
-haplotypes with broad and potent antigen presentation
-increased risk of persistent immune responses and autoreactivity
-implicated in MS, lupus, RA, T1D, and most autoimmune diseases, including ME/CFS, long COVID, and post-vaccinal syndromes

We proposed that these same haplotypes also shape the immune response to EBV, favoring viral persistence and prolonged inflammation.
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1710571/full

The new study provides important validation

This new work on EBV confirms—through a different approach—exactly the same model:
Viral persistence + specific HLA-II antigen presentation → chronic immune activation → loss of tolerance → autoimmune phenomena

This is the same pathogenic sequence we had previously proposed for:
-ME/CFS
-long COVID
-post-viral syndromes
-autoimmune diseases

A shared framework: emerging autoimmune diseases driven by antigen persistence
The convergence of evidence supports that:
-ME/CFS
-long COVID
-post-vaccinal syndromes in predisposed individuals
-post-infectious syndromes

share features of emerging autoimmune diseases, in which:

-there is an infectious trigger (often EBV, SARS-CoV-2, or intracellular pathogens with immune evasion mechanisms)
-antigen persistence occurs
-ancestral host HLA-II shapes the immune response
-loss of tolerance and autoreactivity develop

Clinical implication: HLA-II typing as a preventive tool
Taken together, these studies point in a clear direction:

HLA-II haplotype typing should be incorporated into:
-patients with persistent viral infections
-ME/CFS
-long COVID
-post-infectious inflammatory syndromes
-individuals at risk of autoimmunity after infections

Because it allows us to:
-identify susceptibility to viral persistence
-anticipate the risk of chronic immune dysfunction
-stratify patients for early follow-up
-move toward preventive immunogenetic medicine

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[Utsikt]

Population-scale sequencing resolves determinants of persistent EBV DNA, 2026, Nyeo et al

Population-scale sequencing resolves determinants of persistent EBV DNA

Spoiler: Authors

Nyeo, Sherry S.; Cumming, Erin M.; Burren, Oliver S.; Pagadala, Meghana S.; Gutierrez, Jacob C.; Ali, Thahmina A.; Kida, Laura C.; Chen, Yifan; Chu, Hoyin; Hu, Fengyuan; Zou, Xueqing Zoe; Hollis, Benjamin; Fabre, Margarete A.; MacArthur, Stewart; Wang, Quanli; Ludwig, Leif S.; Dey, Kushal K.; Petrovski, Slavé; Dhindsa, Ryan S.; Lareau, Caleb A.

Abstract
Abstract Epstein–Barr virus (EBV) is an endemic herpesvirus implicated in autoimmunity, cancer and neurological disorders. Although primary infection is often subclinical, persistent EBV infection can drive immune dysregulation and long-term complications. Despite the ubiquity of infection, the determinants of EBV persistence following primary exposure remain poorly understood, although human genetic variation partially contributes to this phenotypic spectrum 1–3 .

Here we demonstrate that existing whole genome sequencing (WGS) data of human populations can be used to quantify persistent EBV DNA. Using WGS and health record data from the UK Biobank ( n = 490,560) and All of Us ( n = 245,394), we uncover reproducible associations between blood-derived EBV DNA quantifications and respiratory, autoimmune, neurological and cardiovascular diseases.

We evaluate genetic determinants of persistent EBV DNA via genome association studies, revealing heritability enrichment in immune-associated regulatory regions and protein-altering variants in 148 genes. Single-cell and pathway level analyses of these loci implicate variable antigen processing as a primary determinant of EBV DNA persistence.

Further, relevant gene programs were enriched in B cells and antigen-presenting cells, consistent with their roles in viral reservoir and clearance.

Human leukocyte antigen genotyping and predicted viral epitope presentation affinities implicate major histocompatibility complex class II variation as a key modulator of EBV persistence.

Together, our analyses demonstrate how re-analysis of human population-scale WGS data can elucidate the genetic architecture of viral DNA persistence, a framework generalizable to the broader human virome 4 .

Web | DOI | PDF | Nature

 

[jnmaciuch]

interesting that levels of EBV DNA in the blood had such a strong association with HLA. That’s an example of an “MHC skyscraper” that we were talking about before DecodeME results came out.

In addition to the viral clearance hypotheses considered by the authors, it also ought to be mentioned that EBV uses HLA for viral entry, so the association might just reflect greater rates of infection and establishment of latency in B cells with certain haplotypes. [Edit: I’m wondering if that is another way to make sense of the negative correlation with antigen binding affinity—membrane fusion could actually be interrupted by binding affinity that is too strong, perhaps]

Since there was no DecodeME signal in HLA nearly as strong as this association, I think that’s another strong piece of negative evidence against ME/CFS being driven by persistent EBV