Category: Viruses

Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease?

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness with unknown etiology. An estimated 17-24 million people representing approximately 1% of the population are afflicted worldwide. In over half of cases, ME/CFS onset is associated with acute “flu-like” symptoms, suggesting a role for viruses. However, no single virus has been identified as the only etiological agent.

This may reflect the approach employed or more strongly the central dogma associated with herpesviruses replication, which states that a herpesvirus exists in two states, either lytic or latent. The purpose of this review is to address the role that abortive lytic replication may have in the pathogenesis of ME/CFS and other post-acute viral infections and also to raise awareness that these syndromes might be poly-herpesviruses mediated diseases.

Source: Ariza ME, Mena Palomo I, Williams MV. Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease? Viruses. 2025 Dec 16;17(12):1624. doi: 10.3390/v17121624. PMID: 41472292. https://www.mdpi.com/1999-4915/17/12/1624 (Full text)

Chronic Reactivation of Persistent Human Herpesviruses EBV, HHV-6 and VZV and Heightened Anti-dUTPase IgG Antibodies Are a Recurrent Hallmark in Post-Infectious ME/CFS and is Associated With Fatigue

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with unknown etiology and heterogeneous symptomology for which there are no validated tests for definitive diagnosis. We examined 873 longitudinal serum samples from ME/CFS patients (n = 40) and 378 from healthy control individuals (n = 16) for differences in human herpesvirus and endogenous retrovirus-K (HERV-K) dUTPase IgG antibodies by ELISA.

The results of this study demonstrate a significant increase in dUTPase IgG antibodies to the herpesviruses Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6) and varicella zoster virus (VZV) in ME/CFS compared to healthy-controls (p < 0.001). Notably, 72.5% (n = 29) of ME/CFS patients simultaneously co-expressed antibodies to multiple herpesvirus and HERV-K dUTPases compared to 31% (n = 5) of the healthy controls. Chi-square test analysis showed strong associations for EBV, HHV-6 and VZV dUTPase antibodies seropositivity (p < 0.001) and Spearman correlation analysis revealed significant positive associations of EBV and HHV-6 dUTPase IgG antibodies with fatigue.

Further examination of the distribution of dUTPase antibodies across fatigue severity groups show that heightened dUTPase IgG levels cluster with ME/CFS patients exhibiting moderate and severe fatigue. These findings highlight the importance of examining herpesvirus dUTPase IgG across severity groups in aiding with current challenges for stratifying ME/CFS patients due to the heterogeneity in symptomology.

Source: Palomo IM, Cox B, Williams MV, Ariza ME. Chronic Reactivation of Persistent Human Herpesviruses EBV, HHV-6 and VZV and Heightened Anti-dUTPase IgG Antibodies Are a Recurrent Hallmark in Post-Infectious ME/CFS and is Associated With Fatigue. J Med Virol. 2026 Jan;98(1):e70769. doi: 10.1002/jmv.70769. PMID: 41451845. https://pubmed.ncbi.nlm.nih.gov/41451845/

Mucosal Viruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Missing Piece of the Puzzle?

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition without a definitive aetiology, no reliable diagnostic test, and no proven effective treatment. Despite most patients reporting a post-viral onset of illness, findings to date are conflicting on whether a single virus or multiple viral triggers are involved. Most studies to date have focused on detecting viruses in blood and circulating immune cells with relatively few investigating the presence of viruses in mucosal sites.

In this review, we propose that this represents a critical gap in understanding the pathophysiology of ME/CFS knowledge, as mucosal tissues are primary entry points for most pathogens and often serve as reservoirs where viruses may persist. Consequently, they represent ideal niches for identifying persistent infections in ME/CFS. Emerging evidence from saliva and other mucosal samples in ME/CFS patients is consistent with this proposal and that latent viruses can persist and periodically reactivate in mucosal tissues from where they can potentially contribute to immune dysregulation, chronic inflammation, and increased symptom severity that defines ME/CFS.

Source: Perera KD, Cameron P, Sarwar T, Carding SR. Mucosal Viruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Missing Piece of the Puzzle? Int J Mol Sci. 2025 Nov 19;26(22):11161. doi: 10.3390/ijms262211161. PMID: 41303644; PMCID: PMC12652652. https://pmc.ncbi.nlm.nih.gov/articles/PMC12652652/ (Full text)

Virus Genome Sequences in the Blood of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a baffling disease. The disease has a wide spectrum of severity, to date has no established molecular marker, no known causation, and no cure. Many patients report in retrospect that they suffered a virus infection prior to suffering their first symptoms of ME/CFS. Therefore, we report a search for virus genome sequences in the cell-free blood of ME/CFS patients and healthy controls. We used a panel of molecular probes to assess the presence or absence of 185 diverse human viruses in each sample. We identified a total of seventeen viruses, with more in the healthy controls than in the ME/CFS patients.

Source: Hyman RW, Xu W, Roy KR, Suresh S, St Onge RP, Davis RW. Virus Genome Sequences in the Blood of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. medRxiv [Preprint]. 2025 Nov 7:2025.11.06.25339689. doi: 10.1101/2025.11.06.25339689. PMID: 41282945; PMCID: PMC12637746. https://pmc.ncbi.nlm.nih.gov/articles/PMC12637746/ (Full text available as PDF file)

HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity

Abstract:

Research of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM), two acquired chronic illnesses affecting mainly females, has failed to ascertain their frequent co-appearance and etiology. Despite prior detection of human endogenous retrovirus (HERV) activation in these diseases, the potential biomarker value of HERV expression profiles for their diagnosis, and the relationship of HERV expression profiles with patient immune systems and symptoms had remained unexplored.

By using HERV-V3 high-density microarrays (including over 350k HERV elements and more than 1500 immune-related genes) to interrogate the transcriptomes of peripheral blood mononuclear cells from female patients diagnosed with ME/CFS, FM, or both, and matched healthy controls (n = 43), this study fills this gap of knowledge. Hierarchical clustering of HERV expression profiles strikingly allowed perfect participant assignment into four distinct groups: ME/CFS, FM, co-diagnosed, or healthy, pointing at a potent biomarker value of HERV expression profiles to differentiate between these hard-to-diagnose chronic syndromes.

Differentially expressed HERV-immune-gene modules revealed unique profiles for each of the four study groups and highlighting decreased γδ T cells, and increased plasma and resting CD4 memory T cells, correlating with patient symptom severity in ME/CFS. Moreover, activation of HERV sequences coincided with enrichment of binding sequences targeted by transcription factors which recruit SETDB1 and TRIM28, two known epigenetic silencers of HERV, in ME/CFS, offering a mechanistic explanation for the findings.

Unexpectedly, HERV expression profiles appeared minimally affected in co-diagnosed patients denoting a new nosological entity with low epigenetic impact, a seemingly relevant aspect for the diagnosis and treatment of this prevalent group of patients.

Source: Giménez-Orenga K, Martín-Martínez E, Nathanson L, Oltra E. HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity. Elife. 2025 May 8;14:RP104441. doi: 10.7554/eLife.104441. PMID: 40338225. https://elifesciences.org/articles/104441 (Full text)

Predisposing and Precipitating Factors in Epstein–Barr Virus-Caused Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Long COVID following SARS-CoV-2 and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) following infectious mononucleosis (IM) are two examples of post-viral syndromes. The identification of risk factors predisposing patients to developing and maintaining post-infectious syndromes may help uncover their underlying mechanisms.
The majority of patients with ME/CFS report infectious illnesses before the onset of ME/CFS, with 30% of cases of ME/CFS due to IM caused by the Epstein–Barr virus. After developing IM, one study found 11% of adults had ME/CFS at 6 months and 9% had ME/CFS at 1 year. Another study of adolescents found 13% and 7% with ME/CFS at 6 and 12 months following IM, respectively. However, it is unclear which variables are potential risk factors contributing to the development and maintenance of ME/CFS following IM, because few prospective studies have collected baseline data before the onset of the triggering illness.
The current article provides an overview of a study that included pre-illness predictors of ME/CFS development following IM in a diverse group of college students who were enrolled before the onset of IM. Our data set included an ethnically and sociodemographically diverse group of young adult students, and we were able to longitudinally follow these youths over time to better understand the risk factors associated with the pathophysiology of ME/CFS.
General screens of health and psychological well-being, as well as blood samples, were obtained at three stages of the study (Stage 1—Baseline—when the students were well, at least 6 weeks before the student developed IM; Stage 2—within 6 weeks following the diagnosis of IM, and Stage 3—six months after IM, when they had either developed ME/CFS or recovered). We focused on the risk factors for new cases of ME/CFS following IM and found factors both at baseline (Stage 1) and at the time of IM (Stage 2) that predicted nonrecovery. We are now collecting seven-year follow-up data on this sample, as well as including cases of long COVID. The lessons learned in this prospective study are reviewed.
Source: Jason LA, Katz BZ. Predisposing and Precipitating Factors in Epstein–Barr Virus-Caused Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Microorganisms. 2025; 13(4):702. https://doi.org/10.3390/microorganisms13040702 https://www.mdpi.com/2076-2607/13/4/702 (Full text)

Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome

Abstract:

Background: Etiology remains elusive for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and no treatment exists. Antivirals had no efficacy in randomized clinical trials (RCT) for Epstein-Barr Virus and HHV-6. Enteroviruses (EV) have been implicated, but no antivirals are available. Many patients who received SARS–CoV-2-specific antiviral drugs for acute Covid-19 (COV19) infection experienced significant improvement of prior ME/CFS symptoms. This study summarizes their responses to antivirals for SARS-Cov-2.
Methods: Neutralizing Antibody (NA) for Coxsackievirus B (CVB)1-6 and Echovirus 6, 7, 9, 11, 30 were done by ARUP lab. Enterovirus Protein (EVP) of Peripheral Blood Leukocytes (PBL) was determined by Western Blot. ME/CFS patients fulfilled Canadian consensus criteria, and had either elevated NA for enteroviruses and/or positive EVP in PBL. ME/CFS patients hospitalized for acute COV19 infection and patients without COV19, were given 5-10 days of IV Remdesivir (Rem) +/- immune modulators. Controls: 20 ME/CFS patients seen concurrently without Remdesivir treatment. Other ME/CFS patients (non-COV19) were given Nirmaltrelvir/Ritonavir (PAX) daily for 10 days +/- one repeat. The energy index (EI) was monitored by the patients before, during and after treatment. Significant improvement was defined as > 30%.
Results: 15/20 (75%) ME/CFS patients – 10/12 hospitalized, 5/8 non-COV19 patients – responded to IV Rem 2-6 weeks after infusions; remission lasted 6-8 weeks to 6-9 months before relapse. Of Controls: 2/20 had mild improvement (< 0.001, X 2 ).

104/200 (52%) of PAX-treated ME/CFS patients improved, often within 2-3 days; all relapsed within days to weeks after treatment. 66%, 33% and 44% of CVB4+, CVB3+, non-CVB3,4+ patients responded to treatment, respectively. EVP decreased and increased with clinical response and relapse.

Conclusion: Rem and PAX demonstrated clinical efficacy in ME/CFS patients with chronic enterovirus infections. Placebo-controlled RCT will be needed to clarify the role of antivirals in ME/CFS.
Source: John K Chia, David Wang, P-2363. Efficacy Of SARS–CoV-2 Specific Antiviral Therapy for Enteroviral Myalgic Encephalomyelitis/ChronicFatigue Syndrome, Open Forum Infectious Diseases, Volume 12, Issue Supplement_1, February 2025, ofae631.2514, https://doi.org/10.1093/ofid/ofae631.2514 https://academic.oup.com/ofid/article/12/Supplement_1/ofae631.2514/7988721?login=false 

Over-Representation of Torque Teno Mini Virus 9 in a Subgroup of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disorder classified by the WHO as postviral fatigue syndrome (ICD-11 8E49 code). Diagnosing ME/CFS, often overlapping with fibromyalgia (FM), is challenging due to nonspecific symptoms and lack of biomarkers. The etiology of ME/CFS and FM is poorly understood, but evidence suggests viral infections play a critical role. This study employs microarray technology to quantitate viral RNA levels in immune cells from ME/CFS, FM, or co-diagnosed cases, and healthy controls.

The results show significant overexpression of the Torque Teno Mini Virus 9 (TTMV9) in a subgroup of ME/CFS patients which correlate with abnormal HERV and immunological profiles. Increased levels of TTMV9 transcripts accurately discriminate this subgroup of ME/CFS patients from the other study groups, showcasing its potential as biomarker for patient stratification and the need for further research into its role in the disease. Validation of the findings seems granted in extended cohorts by continuation studies.

Source: Giménez-Orenga K, Martín-Martínez E, Oltra E. Over-Representation of Torque Teno Mini Virus 9 in a Subgroup of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study. Pathogens. 2024 Sep 1;13(9):751. doi: 10.3390/pathogens13090751. PMID: 39338942; PMCID: PMC11435283. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11435283/ (Full text)

Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease presenting with severe fatigue, post-exertional malaise, and cognitive disturbances-among a spectrum of symptoms-that collectively render the patient housebound or bedbound. Epigenetic studies in ME/CFS collectively confirm alterations and/or malfunctions in cellular and organismal physiology associated with immune responses, cellular metabolism, cell death and proliferation, and neuronal and endothelial cell function.

The sudden onset of ME/CFS follows a major stress factor that, in approximately 70% of cases, involves viral infection, and ME/CFS symptoms overlap with those of long COVID. Viruses primarily linked to ME/CFS pathology are the symbiotic herpesviruses, which follow a bivalent latent-lytic lifecycle. The complex interaction between viruses and hosts involves strategies from both sides: immune evasion and persistence by the viruses, and immune activation and viral clearance by the host. This dynamic interaction is imperative for herpesviruses that facilitate their persistence through epigenetic regulation of their own and the host genome.

In the current article, we provide an overview of the epigenetic signatures demonstrated in ME/CFS and focus on the potential strategies that latent viruses-particularly Epstein-Barr virus-may employ in long-term epigenetic reprograming in ME/CFS. Epigenetic studies could aid in elucidating relevant biological pathways impacted in ME/CFS and reflect the physiological variations among the patients that stem from environmental triggers, including exogenous viruses and/or altered viral activity.

Source: Apostolou E, Rosén A. Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses. J Intern Med. 2024 May 1. doi: 10.1111/joim.13792. Epub ahead of print. PMID: 38693641. https://onlinelibrary.wiley.com/doi/10.1111/joim.13792 (Full text)

Prevalence of persistent SARS-CoV-2 in a large community surveillance study

Abstract:

Persistent SARS-CoV-2 infections may act as viral reservoirs that could seed future outbreaks1-5, give rise to highly divergent lineages6-8 and contribute to cases with post-acute COVID-19 sequelae (long COVID)9,10. However, the population prevalence of persistent infections, their viral load kinetics and evolutionary dynamics over the course of infections remain largely unknown.

Here, using viral sequence data collected as part of a national infection survey, we identified 381 individuals with SARS-CoV-2 RNA at high titre persisting for at least 30 days, of which 54 had viral RNA persisting at least 60 days. We refer to these as ‘persistent infections’ as available evidence suggests that they represent ongoing viral replication, although the persistence of non-replicating RNA cannot be ruled out in all.

Individuals with persistent infection had more than 50% higher odds of self-reporting long COVID than individuals with non-persistent infection. We estimate that 0.1-0.5% of infections may become persistent with typically rebounding high viral loads and last for at least 60 days. In some individuals, we identified many viral amino acid substitutions, indicating periods of strong positive selection, whereas others had no consensus change in the sequences for prolonged periods, consistent with weak selection. Substitutions included mutations that are lineage defining for SARS-CoV-2 variants, at target sites for monoclonal antibodies and/or are commonly found in immunocompromised people11-14. This work has profound implications for understanding and characterizing SARS-CoV-2 infection, epidemiology and evolution.

Source: Ghafari M, Hall M, Golubchik T, Ayoubkhani D, House T, MacIntyre-Cockett G, Fryer HR, Thomson L, Nurtay A, Kemp SA, Ferretti L, Buck D, Green A, Trebes A, Piazza P, Lonie LJ, Studley R, Rourke E, Smith DL, Bashton M, Nelson A, Crown M, McCann C, Young GR, Santos RAND, Richards Z, Tariq MA, Cahuantzi R; Wellcome Sanger Institute COVID-19 Surveillance Team; COVID-19 Infection Survey Group; COVID-19 Genomics UK (COG-UK) Consortium; Barrett J, Fraser C, Bonsall D, Walker AS, Lythgoe K. Prevalence of persistent SARS-CoV-2 in a large community surveillance study. Nature. 2024 Feb 21. doi: 10.1038/s41586-024-07029-4. Epub ahead of print. PMID: 38383783. https://www.nature.com/articles/s41586-024-07029-4 (Full text)