COVID-19 can wake up dormant viruses in the body, large study confirms

Early in the COVID-19 pandemic, scientists noticed that a SARS-CoV-2 infection can “wake up” other, dormant viruses already present in the body. A study out today in Nature extends those and subsequent observations, documenting viral reactivation for a cohort of more than 1000 patients hospitalized with COVID-19 before mid-2021.

The findings provide a detailed picture of the hidden viruses that become active at different points of a SARS-CoV-2 infection, and link reactivation of some of them to more severe COVID-19 and to lingering symptoms, such as fatigue, that are the hallmark of Long Covid.

Although the study can’t prove virus reactivation causes these outcomes, it has impressed some SARS-CoV-2 researchers. “The scale of the endeavor and the range of human viruses they’ve looked at” makes this the most comprehensive data set yet on viral reactivation in COVID-19, says Danny Altmann, an immunologist at Imperial College London who was not involved in the work. The findings, which were partially described in a preprint in late 2024, include data on viruses previously overlooked in COVID-19 patients, he adds.

The human body is usually efficient at clearing viruses. But some, such as the Epstein-Barr virus (EBV), a herpesvirus that causes mononucleosis, stick around quietly in pockets of cells called reservoirs, until certain illnesses or other stressors unleash them. In COVID-19 patients, scientists have documented numerous instances of reactivation of EBV and other herpesviruses, including cytomegalovirus (CMV), which causes flulike symptoms in some people.

Whether these reactivated viruses affect the health of people with COVID-19 remains unclear. Prior research has found connections between EBV reactivation and symptoms of Long Covid, leading some scientists to propose that herpesviruses help drive that condition. But most studies have been limited in size—no more than a few hundred participants—or have focused on just one or two viruses, notes Esther Melamed, a neuroimmunologist at the University of Texas at Austin and co-author on the new study.

Melamed’s team tried a broader approach. The researchers took advantage of a study they and other investigators launched in 2020 to collect symptom reports and tissue samples including blood and nasal swabs from 1154 people with severe COVID-19 during the 12 months following their hospitalization. The researchers scanned gene transcript data from these samples to look for signs of active viruses—and found much more than SARS-CoV-2. “Nearly half of people … had a virus that they were already carrying wake up,” Melamed says. “This happens [even] in people whose immune systems are otherwise normal.”

EBV and CMV showed up frequently in the samples, albeit at different points in the course of COVID-19: EBV was often detected at hospitalization, whereas CMV detections spiked a few weeks later. Anelloviruses, a group of extremely widespread, seemingly harmless human viruses, were also common around the time of hospitalization and several weeks afterward. Reactivation of any of these viruses was associated with more severe COVID-19 in those early weeks, the data showed.

The researchers also compared virus reactivation and longer term symptoms such as fatigue or brain fog. Unlike earlier studies, they didn’t detect a link between EBV and these signs of Long Covid. (The discrepancy could be because of differences in how viral presence is measured: Earlier studies often used antibody-based detection rather than gene transcripts, Melamed notes.) But the team did find an association between anellovirus reactivation and fatigue or other physical challenges.

The study couldn’t determine whether anelloviruses help cause these Long Covid symptoms. But Melamed highlights another finding from the study: The presence of reactivated anellovirus in a sample was associated with higher activity in certain white blood cells. That suggests these viruses “may not be entirely passive bystanders, but are actually contributing to immune dysregulation,” she says.

Other researchers caution the study involved unvaccinated people infected with early SARS-CoV-2 strains who ended up hospitalized. The findings’ relevance for everyone else, then and now, is less clear. “These are critically ill people that are sick with a very inflammatory virus,” says Timothy Henrich, an infectious diseases researcher at the University of California San Francisco. It’s not surprising other viruses become reactivated among people in this weakened state, he adds.

He and Melamed agree the only way to demonstrate a role for virus reactivation in Long Covid is to test whether drugs that block reawakening prevent or improve the condition—a question Melamed says her team hopes to address in a clinical trial.

Other research might offer clues in the meantime. Researchers at the Icahn School of Medicine at Mount Sinai are already testing Truvada, an antiviral widely used against HIV that may also inhibit EBV replication, in a small study of Long Covid patients. Expected to wrap up later this year, the trial is “intended to probe a plausible hypothesis” rather than find treatment at this stage, says Yale University immunologist Akiko Iwasaki, who is helping run it. “That would require a much larger study.”

So far, Long Covid has been blamed on everything from autoimmune-like responses to so-called microclots to trace amounts of SARS-CoV-2 that persist beyond initial infection. Altmann says he’s pleased to see the possible role of virus reactivation getting attention amid this complicated debate. “It’s all kind of up in the air at the moment,” he says. “It’s worth revisiting any viable candidates.”