Endogenous Retroviruses and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

/Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by persistent fatigue, post-exertional malaise (PEM), and cognitive impairment. Viral infections have long been suspected of as potential triggers; however, no specific exogenous pathogen has been consistently identified. Patients with ME/CFS exhibit heightened immune responses and systemic inflammation, suggesting underlying immune dysfunction. A promising yet largely unexplored avenue of research involves endogenous retroviruses (ERVs), which comprise approximately 8% of the human genome as remnants of ancient viral infections. Although typically silenced, ERVs can be reactivated by various triggers, including viral infections, leading to heightened immune responses and inflammation. This suggests a potential link between ERVs and ME/CFS. The long-term goal of this research is to elucidate the underlying causes of ME/CFS and identify novel diagnostic biomarkers and therapeutic targets. The primary objective of this study is to establish connections between ERVs and ME/CFS by identifying specific ERVs associated with ME/CFS diagnosis and PEM. To achieve this, the research team will employ novel methodologies, including the latest ERVcaller platform for highly accurate detection of distinct individual ERVs. This study will analyze extensive datasets, including RNA sequencing (RNA-Seq), whole-genome sequencing (WGS), and single-cell RNA sequencing (scRNA-Seq), making it the largest ERV study in ME/CFS to date. This objective will be pursued through three Specific Aims: (1) identifying ERVs whose expression is associated with ME/CFS using RNA-Seq data from ME/CFS patients and sedentary healthy controls, as well as ERVs that co-occur with PEM before and after an exercise challenge; (2) identifying ERV variants associated with ME/CFS susceptibility using WGS data from patients and matched controls, with independent validation in large WGS datasets from the All of Us program; and (3) mapping ERVs at the single-cell level using scRNA-Seq data to pinpoint specific cell types in which ERV expression correlates with ME/CFS. Completion of these Aims will provide a multidimensional understanding of the ERV-ME/CFS relationship at both transcriptomic and genomic levels. Expected outcomes include the identification of specific individual ERV transcripts and variants associated with ME/CFS, as well as a comprehensive map of ERV expression across cell types. These findings will lay the groundwork for future investigations into the functional roles and potential causal mechanisms of specific ERVs in ME/CFS. Ultimately, this research could inform novel diagnostic and therapeutic strategies, including antiretroviral and anti-inflammatory treatments, with the potential to mitigate ERV activation and alter disease progression. Project Number: 1R01AI196738-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Dawei Li | Institution: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER, LUBBOCK, TX | Award Amount: $388,229 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CFS-W (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19673801