COVID-19 Reactivates Dormant Viruses, Offering New Clues to Long COVID

Chronically infecting viruses—such as Epstein Barr, cytomegalovirus, and herpes virus—are ubiquitous in humans. Although their presence is often innocuous and asymptomatic, the viruses can reactivate during stress, and emerging evidence suggests that their reactivation may contribute to autoimmune disease and other chronic conditions. SARS-CoV-2 infection is known to reactivate some chronic viruses, yet the full extent of the effects is not well understood.

Now, a study including 15 biomedical research institutions across the United States, Boston Children’s Hospital researchers and their collaborators have discovered that COVID-19 reactivates certain dormant viruses in hospitalized patients. These findings expand understanding of chronically infecting viruses and could inform development of strategies to combat their reactivation.

This work is published in a new study in Nature, entitled, “Virus reactivation in acute and long COVID-19.”

The study leveraged multiomic longitudinal data of 1,154 patients with COVID-19 from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study across 20 U.S. biomedical research hospitals. It was designed to define biomarkers of COVID-19 severity and outcomes.

“This is the largest and most comprehensive biomarker study of COVID-19, in which we followed more than one thousand patients, collected more than 200,000 samples, and generated more than one billion data points over the course of a year for this public resource,” says Joann Diray Arce, PhD, who leads the PVP-Data Management and Analysis Core and is the lead of the study’s Clinical and Data Coordinating Center.

The research team detected 11 reactivated viruses in patients within the first 40 days from admission, with the most detected ones being Epstein-Barr, herpes simplex 1, cytomegalovirus, and Anelloviridae viruses. Notably, reactivation of Anelloviridae, a poorly understood family of viruses typically latent in about 90 percent of the population, was associated prominently with long-term physical disability and long COVID.

“This association with long COVID is an interesting finding as millions around the world suffer from this chronic condition,” says Ofer Levy, MD, PhD, director of the Precision Vaccines Program (PVP) at Boston Children’s. “Having new insight as to the molecular and viral associations with long COVID could point the way to better understanding and ultimately better diagnostics and treatments.”

In an analysis of the blood samples from the patients, Epstein-Barr and cytomegalovirus seemed to activate in response to inflammation rather than immune system suppression.  The researchers say this is a surprising new mechanism, challenging the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression. This finding demonstrates that reactivations occur frequently in apparently immunocompetent individuals during severe illness and in association with increased systemic inflammation.

In addition, the authors write, the 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.” They also demonstrate persistence of viral reactivation in convalescence and report an association of Anelloviridae with long COVID.

“Although many no longer think of COVID being a problem, up to 50,000 Americans died of COVID in 2025-2026 respiratory season and some estimates suggest over 10 million U.S. adults suffer from long COVID,” says Levy. “We need to help these patients recover with the best outcomes.” He adds “Moreover, sooner or later, there may be another coronavirus pandemic, which means we need to learn all the lessons we can from COVID-19 to be better prepared.”

Next steps for this work will be to uncover how the immune system responds to these viruses over the course COVID-19, with the aim of identifying effective therapeutics and establishing the optimal timing of any interventions.

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