HLA and pathogens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other post-infection conditions

4 min read

Georgopoulos et al. (2025)
  • Authors: Apostolos P. Georgopoulos, Lisa M. James, Philip K. Peterson.
  • Institutes: The HLA and Chronic Diseases Research Groups, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis VAMC; Department of Neuroscience, University of Minnesota Medical School; Institute for Health Informatics, University of Minnesota Medical School; Department of Psychiatry, University of Minnesota Medical School; Department of Medicine, University of Minnesota Medical School.
  • Publisher: Scientific Reports.
  • Link: DOI.

Summary

This computational study offers a potential genetic explanation for why some individuals develop ME/CFS after a viral infection while others recover. It suggests the risk may depend on how a person’s specific immune system genes (their HLA type) equip them to “grab” and clear out the infection. The finding that ME/CFS “risk” genes are poor at binding to herpesvirus proteins supports the “persistent antigen” hypothesis, where leftover parts of the virus may remain in the body, driving chronic symptoms. This research is significant because it suggests a common underlying mechanism for ME/CFS, Long COVID, and post-Lyme disease, which could help unify research and diagnostic strategies for these overlapping conditions.

What was researched?

This study investigated the link between specific Human Leukocyte Antigen (HLA) alleles (gene variants) that are known to either increase risk for or protect against ME/CFS. The researchers tested the hypothesis that this risk or protection is directly related to how strongly these specific HLA molecules can bind to antigens (protein fragments) from Human Herpes Viruses (HHV), which are often implicated in ME/CFS.

Why was it researched?

Viral infections are widely suspected as a trigger for ME/CFS , and separate research has identified a genetic component related to HLA alleles. This study aimed to connect these two observations, proposing that an individual’s specific HLA “immunogenetic makeup” modulates their immune response to a viral insult. The hypothesis was that poor HLA binding might allow viral antigens to persist, contributing to chronic illness.

How was it researched?

This was an in silico (computational) study that predicted the binding strength (affinity) of specific HLA alleles to pathogen proteins. The researchers analyzed two HLA alleles associated with ME/CFS susceptibility (C07:04, DQB103:03) and two associated with protection (B08:01, DPB102:01). They tested the binding of these alleles against over 10,000 antigens from the 9 Human Herpes Viruses. The analysis was then extended to pathogens linked to Long COVID (SARS-CoV-2) and post-treatment Lyme disease syndrome (PTLDS) (Borrelia burgdorferi).

What has been found?

The study found that the ME/CFS “susceptibility” (risk) alleles had significantly weaker binding affinity to all HHV antigens compared to the “protective” alleles (). None of the HHV antigens showed strong binding to the risk alleles, whereas the protective alleles showed strong bindings. This same pattern was observed for the other pathogens: the ME/CFS risk alleles also had very weak binding to SARS-CoV-2 and Borrelia burgdorferi proteins, while the ME/CFS protective alleles showed strong bindings.

Discussion

The authors note several limitations of the study. The analyses were limited to only 4 specific HLA alleles that were previously identified. It is possible that other HLA alleles not investigated in this study may also contribute to ME/CFS risk or protection. Similarly, the study focused on HHVs, but the authors acknowledge it is likely that weak HLA binding to other pathogens (e.g., enteroviruses) may also be involved in ME/CFS.

Conclusion & Future Work

The authors conclude that these findings support the hypothesis that ME/CFS, Long COVID, and PTLDS may share a common cause: persistent pathogenic antigens that the patient’s immune system could not eliminate due to an “inadequate” HLA makeup. They speculate that strong HLA binding protects against ME/CFS by eliminating these antigens, while weak binding allows them to persist and contribute to chronic illness. Future work is implied to investigate other HLA alleles and a wider range of pathogens.