Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the human herpesviruses are back! by Maria Eugenia Ariza in Biomolecules 2021, 11(2), 185; 29 January 2021 [doi.org/10.3390/biom11020185] (This article belongs to the Special Issue Epstein-Barr Virus Disease Mechanisms and Stress Responses)
Review abstract:
Figure 1. Model depicting how the combined effect of environmental insults, and stress in genetically susceptible individuals can trigger neurological, immune and metabolic dysfunction, which together could contribute to the symptomology observed in ME/CFS
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown.
Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome.
New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.
5. Conclusions and Future Directions
It is clear that the lack of a universally accepted clinical criteria has led to multiple discrepancies, problems and confusion as to how to accurately diagnose and stratify patients with ME/CFS. This has severely hampered the pursue of studies to clearly define the environmental and genetic factors that act as triggers or the downstream mechanisms responsible for the development/progression of ME/CFS. Furthermore, numerous studies using small size patient cohorts, which lack the statistical power to achieve reproducible and rigorous results, have further complicated the task of identifying biomarkers/signatures that would be useful for diagnosing patients.
The role of some herpesviruses in the development and evolution of ME/CFS in a subset of patients has also been hampered because of the use of classical serological approaches focused primarily on viral proteins expressed during latency or late in the replicative cycle of these viruses or viral load as indicators for the involvement of herpesviruses in the pathobiology of ME/CFS. Recent studies using more advanced serological approaches as well as mechanistic studies have demonstrated the possible role of the EBV BRRF1 and BLLF3 gene products in ME/CFS pathophysiology.
Future directions should focus on exploring the use of these gene products for the development of novel therapeutics and/or as biomarkers with diagnostic application or disease progression. Additionally, additional studies need to be performed in light of the new evidence showing high level of abortive lytic replication of these viruses to determine whether other early herpesvirus proteins could contribute to the disease process.
Finally, since there is evidence suggesting simultaneous reactivation of multiple herpesviruses in a large percentage of ME/CFS patients, studies should examine whether or not there is cooperative effects between these viruses as well as other viruses within the virome that could contribute to human disease.
