A large study has added another clue to the complicated biological picture behind long COVID, finding that several viruses already present in the body can become active during or after COVID-19.
Researchers analysed 1,154 hospitalised COVID-19 patients across 20 sites, using repeated biological samples to examine the activity of viruses that can persist in the human body. The study found reactivation involving several virus families, including Herpesviridae, Enteroviridae and Anelloviridae during the acute phase of COVID-19.
One finding stood out: persistent activity of Anelloviridae during recovery was associated with post-COVID symptoms, particularly problems with physical functioning and fatigue.
But there is an important caveat. The study demonstrates an association, not proof of causation. It does not establish that reactivated viruses directly cause long COVID.
COVID-19 may disturb the body's viral balance
Some viruses can remain in the body after an initial infection without continuously producing obvious symptoms. When the body's immune system is under significant stress, viral activity can change.
The new research suggests that COVID-19 can coincide with the reactivation of viruses that had previously remained relatively quiet.
Among the viruses detected were Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus 1 and members of the Anelloviridae family. The researchers observed different patterns of viral activity over the course of the illness.
This does not mean that everyone who has had COVID-19 will experience viral reactivation or develop long-term complications.
Anelloviridae was the key finding
The most notable signal involved Anelloviridae, a poorly understood family of viruses commonly detected in humans.
Researchers found that persistent Anelloviridae reactivation during the recovery period was associated with post-acute sequelae of COVID-19 (PASC), particularly physical-function problems and fatigue.
That could eventually help scientists identify biological markers associated with prolonged recovery.
However, it is still unclear whether Anelloviridae activity contributes to long COVID, results from the same underlying biological process or simply reflects another aspect of the illness.
The study involved more than 1,100 patients
The research was based on the IMPACC study, which followed 1,154 hospitalised COVID-19 patients across 20 sites.
Researchers used multiple types of biological samples and genomic and multi-omic analyses to examine viral activity during acute illness and recovery. The study reported significant reactivation of chronic viruses during the first 40 days following hospitalisation.
The researchers then examined how those viral patterns related to disease severity and longer-term outcomes.
Their analysis found relationships between viral reactivation, immune responses and clinical outcomes, with persistent Anelloviridae activity during convalescence showing a notable association with PASC-related physical limitations and fatigue.
Inflammation may also play a role
The findings add to evidence that long COVID is unlikely to have one single biological explanation.
Researchers are investigating several possible mechanisms, including persistent viral material, immune dysregulation, inflammation, vascular changes and autoimmune responses. Nature Immunology research has also identified persistent immune activation and inflammatory pathways in people with long COVID.
This means viral reactivation could potentially be one part of a larger biological process, rather than a standalone explanation for persistent symptoms.
Does this mean dormant viruses cause long COVID?
No — not based on this study.
The research found an association between persistent Anelloviridae reactivation and certain long-COVID outcomes. It did not prove that the viral activity itself causes those symptoms.
This distinction is particularly important because patients with long COVID can have very different symptoms and biological profiles.
The World Health Organization describes post-COVID condition as a condition that can affect multiple body systems after the initial infection, with symptoms including fatigue, breathlessness, muscle or joint pain and sleep problems.
Therefore, the new research should be viewed as another piece of the long-COVID puzzle, rather than a definitive explanation.
Could this change long-COVID diagnosis?
Potentially, but more research is needed.
If particular patterns of viral activity consistently correlate with specific long-term outcomes, they could eventually become useful biomarkers for identifying patients at greater risk of prolonged illness.
The researchers say their findings could help inform future approaches to predicting, preventing or treating post-COVID complications.
That does not mean doctors can currently diagnose long COVID by simply testing for Anelloviridae or other reactivated viruses.
What does this mean for treatment?
There is currently no evidence from this study that people with long COVID should routinely receive treatment aimed at dormant viruses.
Researchers first need to establish whether viral reactivation is:
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a driver of persistent symptoms,
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a consequence of severe COVID-19,
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a marker of immune dysfunction, or
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one component of several processes occurring simultaneously.
Until those questions are answered, treatment decisions should continue to be based on a patient's symptoms and clinical assessment rather than the assumption that viral reactivation is the cause.
Why the findings matter
The study provides evidence that COVID-19 can be accompanied by changes in the activity of viruses that persist in the human body.
More importantly, it identifies a potential link between persistent Anelloviridae activity and long-term physical problems and fatigue.
The finding does not prove that dormant viruses are responsible for long COVID. But it gives researchers another biological pathway to investigate as they try to understand why some people recover from COVID-19 while others continue to experience symptoms months later.
