Severe COVID-19 May Reactivate Dormant Viruses, Study Finds

Severe COVID-19 may reactivate viruses that have remained dormant in the body, even in people with otherwise healthy immune systems, according to a new study.

The reactivated viruses included Epstein-Barr virus (EBV), which can cause mononucleosis; cytomegalovirus (CMV); herpes simplex virus (HSV); and anelloviruses. Anelloviruses are found in the majority of people, although they have not been conclusively shown to cause disease in humans.

In the study, however, persistent anellovirus activity was associated with long-term disability following COVID-19. The findings were published Aug. 5 in Nature.

“This is one of the largest and most carefully conducted studies of its kind,” Anna Cliff, an associate professor of microbiology, immunology and cancer biology at the University of Virginia who was not involved in the research, told Live Science.

The results suggest that severe COVID-19 can disturb the body’s normal control of latent viruses. Once reactivated, these viruses may contribute to inflammation and other complications associated with severe or long COVID, although more research is needed to determine whether they directly cause symptoms.

Viral reactivation during and after COVID-19

Researchers followed 1,154 adults hospitalized with COVID-19 of varying severity for one year. The team collected blood samples and nasal swabs from participants, as well as lung-fluid samples from patients who required ventilators. Samples were taken during the first month after infection and again at 3, 6, 9 and 12 months.

The researchers tested the samples for viral RNA. Detecting viral RNA can indicate that genes from a virus are active, although it does not necessarily prove that the virus is producing new infectious particles.

The results showed that several latent viruses became active during acute SARS-CoV-2 infection, including herpesviruses such as EBV, CMV and HSV, as well as anelloviruses. Each virus appeared to follow a different timeline: EBV and anelloviruses tended to emerge earlier, while CMV and HSV appeared later.

Viral reactivation was also linked to changes in the immune system, metabolism and clinical complications. Nearly half of the participants — 550 of 1,148 people — had evidence of at least one reactivated virus.

Importantly, viral reactivation occurred even among people who did not have known immune deficiencies.

Viral reactivation and long COVID symptoms

After the acute infection ended, some participants developed debilitating symptoms associated with long COVID, including fatigue, reduced ability to perform daily activities, sleep problems, brain fog, heart palpitations and post-exertional malaise.

In people with persistent symptoms, anelloviruses were more likely to remain active after the acute phase of COVID-19. The researchers said this association may provide clues about why some people experience prolonged illness after coronavirus infection.

However, the findings show a correlation rather than proof that viral reactivation causes long COVID. It is also possible that ongoing inflammation, immune-system changes or other effects of SARS-CoV-2 infection contribute to both viral reactivation and long-term symptoms.

One strength of the research was its repeated sampling over 12 months. The investigators also replicated their main findings in a separate group of patients whose blood samples were stored in the Mount Sinai biobank.

How could COVID-19 reactivate dormant viruses?

Viruses such as herpesviruses can remain latent in the body after an initial infection. The immune system normally keeps these viruses under control, preventing them from actively replicating.

Previous research has shown that viral reactivation can occur in healthy people experiencing intense physical or psychological stress. Studies involving astronauts and Antarctic researchers have reported similar patterns of herpesvirus activity during periods of extreme stress.

Esther Melamed, a neuroimmunologist at the University of Texas at Austin, suggested that a serious infection may temporarily redirect the immune system’s attention. When immune defenses are focused on controlling SARS-CoV-2, latent viruses may have an opportunity to become active.

Other possible triggers include lack of sleep, surgery and major physical or emotional stress.

Research from Cliff’s laboratory suggests that inflammatory signals may also directly activate latent viruses. In studies of HSV-1, the virus that commonly causes cold sores, the immune-signaling molecule IL-1 was shown to activate the virus in neurons by making the cells highly excitable. Other studies have suggested that IL-6 may produce similar effects in animal models.

What the findings mean for COVID-19 treatment

Although the researchers found evidence of viral activity, detecting viral RNA is not the same as identifying newly formed infectious virus. The team strengthened its conclusions by examining additional evidence, including EBV antibodies and immune cells associated with the locations where EBV commonly remains in the body.

The study authors said that, if future research confirms a connection between anelloviruses, viral reactivation and long COVID, there may be an urgent need to better understand these viruses and develop targeted antiviral treatments.

Future prospective clinical trials will be needed to determine whether antiviral medicines aimed at reactivated viruses can improve outcomes for people with severe or long-term COVID-19.