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

Andy

Andy

Senior Member (Voting rights)
Preprint, see post #6 for peer-reviewed version.
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Abstract​

Epstein-Barr Virus (EBV) is an endemic herpesvirus implicated in autoimmunity, cancer, and neurological disorders. Though primary infection typically resolves with subclinical symptoms, long-term complications can arise due to immune dysregulation or viral latency, in which EBV DNA is detectable in blood for decades. Despite the ubiquity of this virus, we have an incomplete understanding of the highly variable responses to EBV that range from asymptomatic infection to a trigger for severe disease.

Here, we demonstrate that existing whole genome sequencing (WGS) data contains ample non-human DNA sequences to reconstruct a molecular biomarker of latent EBV infection consistent with orthogonal phenotypes, including viral serology. Using the UK Biobank (n = 490,560) and All of Us (n = 245,394), we uncover reproducible complex trait associations that nominate latent blood-derived EBV DNA as a respiratory, autoimmune, and cardiovascular disease biomarker.

Further, we evaluate the genetic determinants of persistent EBV DNA via genome-wide and exome-wide association studies, uncovering protein-altering variants from 147 genes. Single-cell and pathway-scale enrichment analyses implicate variable antigen processing and presentation as a primary genetic determinant of latent EBV persistence, with gene programs expressed in B cells and antigen-presenting cells. Using predicted viral epitope presentation affinities, we implicate genetic variation in MHC class II as a key modulator of EBV DNA persistence.

Our analyses demonstrate how existing WGS data can derive novel molecular biomarkers, which may generalize to dozens of viruses comprising the blood virome.

Open access
 
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This is really interesting--if HLA alleles come up in DecodeME, my first question would be whether those alleles are known to confer functional susceptibility to latency (or just viral susceptibility in general).

Associations with EBV have definitely come up repeatedly for other chronic illnesses, a few of which they note in the intro. Something I'd be really curious about is if the known HLA alleles associations with those other illnesses are partially attributable to viral susceptibility (rather than the role of T cells in maintaining the disease as is always assumed).
 
This looks like a very cool paper, illustrating the power of whole genome sequencing data. It is impressive that the authors were able to use a new technique to reproduce previously known associations between disease traits and EBV status.

I also wonder if it will be possible to perform analogous virome studies using the data generated from SequenceME. The key difference is that this paper uses data derived from blood samples, whereas the SequenceME data will be derived from saliva.
 
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tralfamadorian97 said:
I also wonder if it will be possible to perform analogous virome studies using the data generated from SequenceME. The key difference is that this paper uses data derived from blood samples, whereas the SequenceME data will be derived from saliva.
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It’s theoretically possible! For EBV at least, since it can infect and establish latency in the epithelial cells of the mouth as well as circulatory B cells. What I don’t know for sure is if you’d be able to get a sufficient quantity of infected cells from a sample swab.

If you’re simply trying to detect the presence of any EBV proviral DNA then my guess is that it could be enough, but you probably couldn’t do anything more detailed than that.
 
I am unimpressed by an abstract that says nothing specific about what was found - just general guff about how great they think their study is.

There has been an obsession with MHC diversity encoding disease susceptibility through antigen presentation of peptides in grooves, and vast amounts have been written on EBV under that assumption. I am not aware of much to support it. The most obvious link between HLA and disease is B27. That has a major protective effect against several viruses as I understand it so presumably not through presentation of any one special peptide.

The link to DR4 in RA is most likely related to citrulline binding, although nobody is quite sure how. Citrullination affects a lot of proteins so it is not an issue of any specific peptide from a specific organism.

DQ associations are interesting because rather few T cells show DQ restricted TCR-nased responses. Nobody knows where DQ is fitting in. Danny Altmann wrote a couple of reviews on this.

The situation for EBV latency is complicated because the latency is mostly DNA incorporated into B cell clones being handed on from clone to clone over time. How that relates to diseases like MS is puzzling but maybe the most likely role for MHC would be in influencing ongoing deletion of such clones by CD57+ T cells. The DQ allele expressed by the B cell might alter its susceptibility to deletion and not necessarily through presentation of a specific peptide since DQ can also contribute to more 'innate' interactions.

I have no had time to look at the full text but I would worry that this a paper that finds what it set out to find based on rather blinkered paradigms.

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Population-scale sequencing resolves determinants of persistent EBV DNA (Nature, 28 January 2026)

We also detected an association with malaise and fatigue (odds ratio = 1.27, P = 2.06 × 10−10), noting that EBV has long been hypothesized as a risk factor for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We also identified significant associations with decreased levels of phosphatidylcholine (P = 2.9 × 10−9) and total choline (P = 5.9 × 10−9), consistent with metabolic studies in patients with ME/CFS. Our results reinforce a potential relationship between EBV and ME/CFS that warrants further examination.
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Scraps of viral DNA in biobank samples reveal secrets of Epstein–Barr virus (Nature News)
This virus infects most of us – but why do only some get very ill? (New Scientist)
 
Chris Ponting reaction at Science Media Centre —

“As a side note, one association they found was between EBV DNA and ‘Malaise and fatigue’ (ICD-10 code R53). After this, they stated “that EBV has long been hypothesized as a risk factor for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)” and “Our results reinforce a potential relationship between EBV and ME/CFS that warrants further examination”. Nevertheless, ME/CFS is not classified under R53 (rather, under G93.3), so this interesting association is not clearly relevant to ME/CFS (which has many other symptoms beyond fatigue), but rather is relevant to asthenia, debility, general physical deterioration, lethargy and tiredness. From their supplementary data, ME/CFS (G93.3) had the opposite effect (i.e., was correlated negatively with EBV DNA levels), albeit not significantly.
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Think these are the results relevant to ME/CFS (taken from Supplementary Table 3 - sheet B AII UKB PheWAS results).

Human readable phenotypeRaw phenotypebetasepnCasesdatasetRootbroad.rootrefined
41202#G933#Postviral fatigue syndrome41202#G933#G93.3 Postviral fatigue syndrome-0.13398970.408733720.7392491976binaryChapter VI Diseases of the nervous systemNervous system0
20002#1482#chronic fatigue syndrome20002#1482#chronic fatigue syndrome-0.11100070.081015880.164339881887binaryChapter VI Diseases of the nervous systemNervous system0
Union#G933#Postviral fatigue syndromeUnion#G933#G93.3 Postviral fatigue syndrome-0.10495610.056400020.059188854025binaryChapter VI Diseases of the nervous systemNervous system0
120010#Ever had chronic Fatigue Syndrome or Myalgic Encephalomyelitis (M.E.)120010-0.04671780.075141280.531616452357binaryChapter VI Diseases of the nervous systemNervous system0
Union#R53#Malaise and fatigueUnion#R53#R53 Malaise and fatigue0.23583380.036369982.06E-108813binaryChapter XVIII Symptoms signs and abnormal clinical and laboratory findings not elsewhere classifiedAbnormal labs1
 
Merged posts

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

Population-scale sequencing resolves determinants of persistent EBV DNA

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
 
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

[Edit: I’ll note that generally the lack of a signal in a GWAS isnt good evidence to rule something out, but given that the strength of the association here is orders of magnitude stronger than even the strongest decodeME signal, it’s pretty safe to expect some robust hint of it if EBV persistence was causal for ME/CFS]
 
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