[HERVs] and [ME/CFS]:[...] Disease Pathogenesis, Immune Dysregulation, and as Potential Biomarkers and Therapeutic Targets, 2026, Perera, Carding+

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Human Endogenous Retroviruses and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Emerging Insights into Their Role in Disease Pathogenesis, Immune Dysregulation, and as Potential Biomarkers and Therapeutic Targets

Perera, Krishani Dinali; Garcia, Elisa Oltra; Carding, Simon R.

Abstract
Human endogenous retroviruses (HERVs) are potential driving forces of the pathophysiology of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), linking post-infectious immune dysfunction to chronic inflammation and immune and neurocognitive dysfunction that are hallmark features of ME/CFS.

Accumulating evidence from related autoimmune diseases and cancers has shown that reactivated HERVs can contribute to disease pathogenesis by amplifying immune activation through viral protein-mediated innate sensing, Long Terminal Repeat (LTR)-driven transcription, and disrupting epigenetic silencing. HERV signatures are therefore promising biomarkers for diagnosis, patient stratification for drug-repurposing trials, and therapy monitoring.

Accumulating evidence suggests a possible correlation between HERV expression and ME/CFS symptom severity, alterations of immune phenotypes, function and inflammatory gene networks. Importantly, locus-specific HERV profiling is a promising approach for distinguishing ME/CFS from overlapping or co-morbid conditions and healthy controls. Furthermore, HERV-targeted antibodies, immune modulators, epigenetic and antiviral interventions offer promise as concomitant therapeutic strategies for ME/CFS.

Additional research incorporating viromics and other-omics validation, functional assays, and HERV-stratified clinical trials is now needed to realise this potential and to transform ME/CFS from a symptom-based syndrome into a mechanism-driven, treatable condition.

Web | DOI | Preprints.org | Preprint

 

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Figure 1. A proposed model of HERV-driven immunometabolic, neuroinflammatory, and neuroendocrine dysfunction in ME/CFS.

Viral infection, inflammation, cellular stress, and pharmacological factors initiate epigenetic derepression and transcriptional activation of silenced HERV loci (e.g., HERV-K/W) in both immune and non-immune cells (including in mucosal sites), leading to the production of HERV proteins and viral-like particles (VLPs).

The release of viral proteins and VLPs acts as persistent antigens and TLR ligands, driving chronic immunometabolic dysfunction, T/NK cell senescence, and pro-inflammatory cytokine release. Increased BBB permeability allows systemic mediators and HERV proteins to trigger microglial activation and neuroinflammation, which manifest as cognitive and sensory symptoms.

Concurrently, persistent inflammatory signalling suppresses the HPA axis (CRH/ACTH inhibition), resulting in hypocortisolism and impaired stress responsiveness.

These intersecting processes create self-reinforcing cycles of HERV reactivation, inflammation, neuroendocrine dysfunction, and relapse–recovery dynamics, culminating in PEM and persistent chronic disease.

Figure 2. Proposed diagnosis and treatment strategy for ME/CFS based on HERV expression.

(A) Clinical diagnosis of ME/CFS, followed by exploratory molecular screening of HERV expression in blood or mucosal samples, could enable stratification of patients into HERV-positive (HERV+) or negative (HERV-) cohorts. Patients within the HERV+ cohort could then be further evaluated to characterise the specific HERV loci involved and may potentially benefit from the proposed personalised interventions outlined in the panel (C).

(B) Mapping HERV activation could uncover disease-specific profiles linked to PEM, neuroinflammation, and immune dysregulation. Isolated LTRs and HERV family-specific patterns identified in patient samples support personalised interventions, including immune-targeted therapies, antivirals, epigenetic regulators, and symptom management.