Tag: HERV

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/

Blood parameters differentiate post COVID-19 condition from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia

Abstract:

Post-COVID-19 condition, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM), are characterized by fatigue, pain, shortness of breath, sleep disturbances, cognitive dysfunction and other symptoms, heavily impacting on patients daily functioning. Moreover, over half of patients end up fulfilling ME/CFS and/or FM clinical criteria after a few months of SARS-CoV-2 infection.

Expression of the toxic human endogenous retrovirus (HERV)-W ENV protein can be induced by viral infection and HERV-W detection was correlated with acute COVID-19 severity and found significantly expressed in post-COVID-19 condition. This study shows that HERV-W ENV may also be present in prepandemic cases of ME/CFS, FM or co-diagnosed with both clinical criteria, suggesting viral participation in these chronic diseases.

To learn whether associated antiviral mechanisms may also show differing patterns of immunological responses, we measured IgM, IgG, IgA and IgE antibody isotypes against SARS-CoV-2 spike and nucleocapsid antigens, the levels of IL-6, IL-8, IL-10, IFNγ and TNFα cytokines, the level of NfL, a neural damage biomarker, as well as some blood cell markers potentially related with fatigue.

Importantly, some of the measured variables showed a capacity to discriminate post-COVID-19 condition cases from all other participants, with 100 % sensitivity and up to 71.9 % specificity providing a new tool for a differential diagnosis between diseases or syndromes with so many overlapping clinical symptoms. Interestingly, the detected markers showed moderate-to-strong correlations with patient symptoms pointing at novel therapeutic opportunities.

Source: Giménez-Orenga K, Pierquin J, Brunel J, Charvet B, Martín-Martínez E, Lemarinier M, Fried S, Lucas A, Perron H, Oltra E. Blood parameters differentiate post COVID-19 condition from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia. Brain Behav Immun Health. 2025 Jul 4;48:101058. doi: 10.1016/j.bbih.2025.101058. PMID: 40726775; PMCID: PMC12302357. https://pmc.ncbi.nlm.nih.gov/articles/PMC12302357/ (Full text)

HERV Dysregulation in a Case of Myalgic Encephalomyelitis and Multiple Sclerosis Responsive to Rituximab

Abstract:

This article summarizes the case of 30-year-old male diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and its longitudinal follow-up, which provided a secondary diagnosis of Multiple Sclerosis (MS) eight years later. The most impactful result was his response to rituximab treatment after the systematic failure of prior treatments.

Although the expression of endogenous retroviral proteins has been associated with autoimmunity, the patient did not show increased expression of the toxic protein HERV (human endogenous retrovirus)-W ENV, a target of the ongoing clinical trials with temelimab in MS and long COVID-19 cases. However, genome-wide HERV transcriptome analysis by high density microarrays clearly revealed a distinct profile in the patient’s blood supportive of an altered immune system.

Limitations of the study include sub-optimal frequency of magnetic resonance imaging to monitor lesion progression, and similarly for reassessment of HERV profiles after rituximab. Overall, the coincidence of HERV alterations and the impactful response to rituximab presents the possibility of additional, more specific, therapeutic targets encoded by other HERV elements yet to be discovered.

Source: Martín-Martínez E, Gil-Perotin S, Giménez-Orenga K, Barea-Moya L, Oltra E. HERV Dysregulation in a Case of Myalgic Encephalomyelitis and Multiple Sclerosis Responsive to Rituximab. Int J Mol Sci. 2025 May 20;26(10):4885. doi: 10.3390/ijms26104885. PMID: 40430026; PMCID: PMC12111851. https://pmc.ncbi.nlm.nih.gov/articles/PMC12111851/ (Full text)

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)

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)

HERV activation segregates ME/CFS from fibromyalgia and defines a novel nosological entity for patients fulfilling both clinical criteria

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia (FM) are chronic diseases with poorly understood pathophysiology and diagnosis based on clinical assessment of unspecific symptoms. The recent post-COVID-19 condition, which shares similarities with ME/CFS and FM, has raised concerns about viral-induced transcriptome changes in post-viral syndromes. Viral infections, and other types of stress, are known to unleash human endogenous retroviruses (HERV) repression that if maintained could lead to symptom chronicity. This study evaluated this possibility for ME/CFS and FM on a selected cohort of female patients complying with diagnosis criteria for ME/CFS, FM, or both, and matched healthy controls (n=43).

The results show specific HERV fingerprints for each disease, confirming biological differences between ME/CFS and FM. Unexpectedly, HERV profiles segregated patients that met both ME/CFS and FM clinical criteria from patients complying only with ME or FM criteria, while clearly differentiating patients from healthy subjects, supporting that the highly prevalent comorbidity condition must constitute a different nosological entity.

Moreover, HERV profiles exposed significant quantitative differences within the ME/CFS group that correlated with differences in immune gene expression and patient symptomatology, supporting ME/CFS patient subtyping and confirming immunological disturbances in this disease. Pending issues include validation of HERV profiles as disease biomarkers of post-viral syndromes and understanding the role of HERV during infection and beyond.

Source: Karen Gimenez-Orenga, Eva Martin-Martinez, Lubov Nathanson, Elisa Oltra. HERV activation segregates ME/CFS from fibromyalgia and defines a novel nosological entity for patients fulfilling both clinical criteria. bioRxiv 2023.10.05.561025; doi: https://doi.org/10.1101/2023.10.05.561025 https://www.biorxiv.org/content/10.1101/2023.10.05.561025v1 (Full text available as PDF file)

 

HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms

Abstract:

Due to the wide scope and persistence of COVID-19´s pandemic, post-COVID-19 condition represents a post-viral syndrome of unprecedented dimensions. SARS-CoV-2, in line with other infectious agents, has the capacity to activate dormant human endogenous retroviral sequences ancestrally integrated in human genomes (HERVs). This activation was shown to relate to aggravated COVID-19 patient´s symptom severity.

Despite our limited understanding of how HERVs are turned off upon infection clearance, or how HERVs mediate long-term effects when their transcription remains aberrantly on, the participation of these elements in neurologic disease, such as multiple sclerosis, is already settling the basis for effective therapeutic solutions. These observations support an urgent need to identify the mechanisms that lead to HERV expression with SARS-CoV-2 infection, on the one hand, and to answer whether persistent HERV expression exists in post-COVID-19 condition, on the other.

The present study shows, for the first time, that the HERV-W ENV protein can still be actively expressed long after SARS-CoV-2 infection is resolved in post-COVID-19 condition patients. Moreover, increased anti-SARS-CoV-2 immunoglobulins in post-COVID-19 condition, particularly high anti-SARS-CoV-2 immunoglobulin levels of the E isotype (IgE), seem to strongly correlate with deteriorated patient physical function (r=-0.8057, p<0.01).

These results indicate that HERV-W ENV antigenemia and anti-SARS-CoV-2 IgE serology should be further studied to better characterize post-COVID-19 condition pathogenic drivers potentially differing in subsets of patients with various symptoms. They also point out that such biomarkers may serve to design therapeutic options for precision medicine in post-COVID-19 condition.

Source: Giménez-Orenga K, Pierquin J, Brunel J, Charvet B, Martín-Martínez E, Perron H, Oltra E. HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms. Front Immunol. 2022 Oct 27;13:1020064. doi: 10.3389/fimmu.2022.1020064. PMID: 36389746; PMCID: PMC9647063.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9647063/ (Full text)

HERV-K and HERV-W transcriptional activity in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/MS) is an incapacitating chronic disease that dramatically compromise the life quality. The CFS/ME pathogenesis is multifactorial, and it is believed that immunological, metabolic and environmental factors play a role. It is well documented an increased activity of Human endogenous retroviruses (HERVs) from different families in autoimmune and neurological diseases, making these elements good candidates for biomarkers or even triggers for such diseases.

METHODS: Here the expression of Endogenous retroviruses K and W (HERV-K and HERV-W) was determined in blood from moderately and severely affected ME/CFS patients through real time PCR.

RESULTS: HERV-K was overexpressed only in moderately affected individuals but HERV-W showed no difference.

CONCLUSIONS: This is the first report about HERV-K differential expression in moderate ME/CFS. Although the relationship between HERVs and ME/CFS has yet to be proven, the observation of this phenomenon deserves further attention.

Source: Rodrigues LS, da Silva Nali LH, Leal COD, Sabino EC, Lacerda EM, Kingdon CC, Nacul L, Romano CM. HERV-K and HERV-W transcriptional activity in myalgic encephalomyelitis/chronic fatigue syndrome. Auto Immun Highlights. 2019 Nov 15;10(1):12. doi: 10.1186/s13317-019-0122-8. eCollection 2019 Dec. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065355/ (Full text)

Activation of Transposable Elements in Immune Cells of Fibromyalgia Patients

Abstract:

Advancements in nucleic acid sequencing technology combined with an unprecedented availability of metadata have revealed that 45% of the human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically necessary. Dysregulation of TEs, including human retroviral endogenous sequences (HERVs) has been shown to associate with several neurologic and autoimmune diseases, including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, no study has yet addressed whether abnormal expression of these sequences correlates with fibromyalgia (FM), a disease frequently comorbid with ME/CFS.

The work presented here shows, for the first time, that, in fact, HERVs of the H, K and W types are overexpressed in immune cells of FM patients with or without comorbid ME/CFS. Patients with increased HERV expression (N = 14) presented increased levels of interferon (INF-β and INF-γ) but unchanged levels of TNF-α. The findings reported in this study could explain the flu-like symptoms FM patients present with in clinical practice, in the absence of concomitant infections. Future work aimed at identifying specific genomic loci differentially affected in FM and/or ME/CFS is warranted.

Source: Ovejero T, Sadones O, Sánchez-Fito T, Almenar-Pérez E, Espejo JA, Martín-Martínez E, Nathanson L, Oltra E. Activation of Transposable Elements in Immune Cells of Fibromyalgia Patients. Int J Mol Sci. 2020 Feb 18;21(4). pii: E1366. doi: 10.3390/ijms21041366. https://www.mdpi.com/1422-0067/21/4/1366 (Full text)

Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins

Abstract:

Myalgic encephalomyelitis (ME) is a debilitating illness of unknown etiology characterized by neurocognitive dysfunction, inflammation, immune abnormalities and gastrointestinal distress. An increasing body of evidence suggests that disruptions in the gut may contribute to the induction of neuroinflammation. Therefore, reports of human endogenous retroviral (HERV) expression in association with neuroinflammatory diseases prompted us to investigate the gut of individuals with ME for the presence of HERV proteins.

In eight out of 12 individuals with ME, immunoreactivity to HERV proteins was observed in duodenal biopsies. In contrast, no immunoreactivity was detected in any of the eight controls. Immunoreactivity to HERV Gag and Env proteins was uniquely co-localized in hematopoietic cells expressing the C-type lectin receptor CLEC4C (CD303/BDCA2), the co-stimulatory marker CD86 and the class II major histocompatibility complex HLA-DR, consistent with plasmacytoid dendritic cells (pDCs). Although the significance of HERVs present in the pDCs of individuals with ME has yet to be determined, these data raise the possibility of an involvment of pDCs and HERVs in ME pathology. To our knowledge, this report describes the first direct association between pDCs and HERVs in human disease.

 

Source: De Meirleir KL, Khaiboullina SF, Frémont M, Hulstaert J, Rizvanov AA, Palotás A, Lombardi VC. Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins. In Vivo. 2013 Mar-Apr;27(2):177-87. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776582/ (Full article)