| Sumario: | Chronic complex conditions such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia (FM), and Post-COVID-19 condition remain among the most disabling and poorly understood disorders in medicine. Their clinical overlap, fluctuating course, and lack of reliable biomarkers have hindered diagnosis and treatment. This thesis investigates human endogenous retroviruses (HERVs) and related viral elements as contributors to disease mechanisms and as candidates for biomarker development. The findings in this thesis show that HERV activation is a consistent feature across these conditions, closely linked to immune dysfunction and symptom severity. In Post-COVID-19, HERV-W ENV protein persisted long after infection, accompanied by atypical antibody profiles, reduced interferon-γ, and altered red blood cell indices, defining a distinct biological signature. ME/CFS displayed broad and heterogeneous retroviral activation that stratified patients into molecular subgroups of differing severity, while FM showed narrower signatures and codiagnosed presented minimal alterations. Integration with immune transcriptomics connected these HERV patterns to disrupted T-cell pathways, reduced γδ T cells, plasma cell expansion, and clinical burden. To assess whether such immune and retroviral disturbances might be influenced by exogenous infections, the virome was analyzed in the same samples. While no differential expression was found for common pathogens, Torque Teno Mini Virus 9 (TTMV9) was enriched in a ME/CFS subgroup with strong HERV activation and immune imbalance. As Anelloviruses typically rise under impaired immune control, this finding suggests that weakened antiviral responses may allow endogenous and exogenous viral elements to persist and reinforce one another. Collectively, the work shows that HERVs are not passive bystanders but active components of ME/CFS, FM, and Post-COVID-19 biology, with implications for both understanding pathogenesis and for developing molecular tools to support clinical management.
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