JOURNAL OF IIMER May 2026 LUNANOVA FELLOWSHIP - RESEARCH IN FOCUS Ancient Viruses, Modern Disease - The Role of Human Endogenous Retroviruses in ME A review published in the International Journal of Molecular Sciences argues that human endogenous retroviruses - ancient viral sequences embedded in our genome - may be active drivers of the biological processes underlying ME. Written by Perera, Oltra and Carding of the Quadram Institute Bioscience and Norwich Research Park, it represents a significant step towards understanding ME as a mechanism-driven, biologically distinct condition. What Are Human Endogenous Retroviruses? Human endogenous retroviruses (HERVs) are the remnants of ancient viral infections that integrated into human DNA millions of years ago. They now make up approximately 8% of the human genome. Under normal conditions they are kept inactive. When that suppression breaks down - through infection, stress, or immune dysfunction - HERVs can reactivate and begin producing viral proteins and RNA. This can amplify immune responses, drive chronic inflammation, and disrupt normal gene regulation. Reactivated HERVs have already been implicated in autoimmune diseases including multiple sclerosis, lupus, and juvenile rheumatoid arthritis. The Link to ME The review proposes that reactivated HERVs are plausible contributors to the hallmark features of ME - persistent post-infectious immune dysfunction, chronic inflammation, and the neurological and cognitive symptoms that characterise the disease. Three principal mechanisms are identified. First, HERV proteins trigger sustained immune responses that may perpetuate the immune activation seen after acute viral infection. Second, HERV elements can act as alternative gene switches, upregulating inflammatory networks in ways consistent with the immune patterns observed in ME. Third, HERV reactivation disrupts the very mechanisms that would normally suppress it, creating a self-reinforcing cycle. The paper draws on evidence from multiple sclerosis research, where a specific endogenous retrovirus has been the most thoroughly studied. The authors argue that the immune and inflammatory changes associated with HERV reactivation closely mirror those documented in ME - including altered natural killer cell function, T-cell exhaustion, and elevated pro-inflammatory cytokines. Viral infections known to trigger ME onset - including SARS-CoV-2, Epstein-Barr virus, and enteroviruses - are also known to reactivate HERVs, providing a coherent molecular link between post-infectious onset and the chronic immune dysregulation that follows. Biomarkers and Treatment Implications ME currently has no validated biological diagnostic test. The review identifies HERV expression patterns as a promising approach for distinguishing ME from healthy controls and from overlapping conditions such as fibromyalgia, long COVID, and depression. If validated, HERV signatures could also provide a quantitative measure of disease severity and a means of monitoring treatment response. On the therapeutic side, the paper identifies several candidate strategies: HERV-targeted antibodies, antiviral agents that suppress HERV activity, immune modulators targeting downstream inflammation, and epigenetic interventions aimed at restoring HERV suppression at source. The authors are careful to present these as directions requiring clinical validation, not established treatments. They specifically call for clinical trials enrolling patients selected on the basis of defined HERV expression profiles as the necessary next step. Invest in ME Research Page 9 of 35
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