Human endogenous retroviruses (HERVs) are ancient retroviral DNA sequences established into germline. They contain regulatory elements and encoded proteins few of which may provide benefits to hosts when co-opted as cellular genes. Their tight regulation is mainly achieved by epigenetic mechanisms which can be altered by environmental factors, e.g. viral infections, leading to HERV activation. Aberrant expression of HERVs associates with neurological disease, such as multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS), inflammatory processes and neurodegeneration. This review summarizes recent advances on the epigenetic mechanisms controlling HERV expression and the pathogenic effects triggered by HERV derepression. The article ends describing new promising therapies targeting HERV elements, one of which, temelimab, has completed phase II trials with encouraging results in treating MS. The information gathered here may turn helpful in the design of new strategies to unveil epigenetic failures behind HERV-triggered disease, opening new possibilities for druggable targets and/or for extending the use of temelimab to treat other associated diseases.

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.

Fibromyalgia (FM), classified by ICD-11 with code MG30.0, is a chronic debilitating disease characterized by wide-spread pain, fatigue, cognitive impairment, sleep and intestinal alterations, among other. FM affects a large proportion of the world-wide population, with increased prevalence among women. The lack of understanding of its etiology and pathophysiology hampers the development of effective treatments. Our group had developed a manual therapy (MT) pressure-controlled custom manual protocol on FM showing hyperalgesia/allodynia, fatigue and patient’s quality of life benefits in a cohort of 38 FM cases (NCT04174300). With the aim of understanding the therapeutic molecular mechanisms triggered by MT, this study interrogated PBMC transcriptomes from FM participants of this clinical trial using RNAseq and RT-qPCR technologies. The results showed that the salt-induced kinase SIK-1 was consistently downregulated by MT in FM, correlating with improvement of patient symptoms. In addition, the study compared the findings in a non-FM control cohort subjected to the same MT protocol evidencing that the changes in SIK1 with MT only occurred in individuals with FM. This positions SIK-1 as a potential biomarker to monitor response to MT, and as a therapeutic target of FM, to be further explored by continuation studies.