Virus reactivation in acute and long COVID-19

Abstract:

Chronic viral infections are ubiquitous in humans, with individuals carrying multiple viruses that can reactivate during physiological stress, including severe illness1. Notably, SARS-CoV-2 infection has been shown to reactivate chronic viruses such as Epstein-Barr virus and cytomegalovirus, yet the full extent, temporal dynamics and immunological impact of viral reactivation in COVID-19 remain incompletely understood2-7.

Here, leveraging multi-omic longitudinal data from 1,154 hospitalized patients with COVID-19 from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, we reveal significant reactivation of Herpesviridae and Anelloviridae during acute COVID-19, with distinct temporal dynamics for different viruses, and demonstrate that reactivation correlates with disease severity, host immune effects and clinical outcomes. Although our results do not establish causation between virus reactivation and clinical outcomes, we highlight the prevalence of chronic viral reactivation during acute COVID-19 and long COVID.

Our findings challenge the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression, demonstrating that reactivations occur frequently in immunocompetent individuals during severe illness and in association with increased systemic inflammation. Additionally, we demonstrate persistence of viral reactivation in convalescence, and report an association of Anelloviridae with long COVID.

This study provides immune, transcriptomic and metabolomic signatures of viral reactivation that could inform future strategies to prognosticate and treat acute COVID-19 and long COVID.

Source: Maguire C, Chen J, Rouphael N, Morse BA, Hoch A, Pickering H, Phan HV, Glascock A, Chu V, Dandekar R; IMPACC Network; Corry D, Kheradmand F, Baden LR, Sekaly RP, McComsey GA, Haddad EK, Cairns CB, Pulendran B, Fernandez-Sesma A, Simon V, Metcalf JP, Agudelo Higuita NI, Messer WB, Davis MM, Nadeau KC, Kraft M, Bime C, Schaenman J, Erle D, Calfee CS, Atkinson MA, Brakenridge SC, Ehrlich LIR, Montgomery RR, Shaw A, Hough CL, Hafler D, Augustine AD, Becker PM, Peters B, Ozonoff A, Kim-Schulze S, Krammer F, Bosinger SE, Eckalbar W, Altman MC, Wilson M, Guan L, Kleinstein SH, Smolen KK, Reed EF, Levy O, Maecker H, Hunt P, Steen H, Diray-Arce J, Langelier CR, Melamed E. Virus reactivation in acute and long COVID-19. Nature. 2026 Aug;656(8128):700-711. doi: 10.1038/s41586-026-10740-z. Epub 2026 Aug 5. PMID: 42557313; PMCID: PMC13489964. https://pmc.ncbi.nlm.nih.gov/articles/PMC13489964/ (Full text)

Over-Representation of Torque Teno Mini Virus 9 in a Subgroup of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study

Abstract:

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. Validation of the findings seems granted in extended cohorts by continuation studies.

Source: Giménez-Orenga K, Martín-Martínez E, Oltra E. Over-Representation of Torque Teno Mini Virus 9 in a Subgroup of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study. Pathogens. 2024 Sep 1;13(9):751. doi: 10.3390/pathogens13090751. PMID: 39338942; PMCID: PMC11435283. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11435283/ (Full text)