Where do viruses hide in the human body?BMJ 2023; 382 doi: https://doi.org/10.1136/bmj.p1156 (Published 04 July 2023) Cite this as: BMJ 2023;382:p1156
Where do known viruses linger in the body?
Virus particles often hide in “immunoprivileged sites” around the human body, also sometimes called sanctuary sites, that our immune systems don’t monitor or protect as closely as the rest of our bodies.1 These include the brain, spinal cord, pregnant uterus, testes, and eyes, for which damage by immune cells would be highly problematic. The testes can harbour Zika2 and Ebola3 viruses, for example.
Viruses such as influenza and SARS-CoV-2 primarily infect the respiratory tract but can move elsewhere. Influenza viruses can persist after infection in people’s intestinal tract and stool,4 through swallowed secretions from the nose and throat or viruses in the blood. HIV is a latent virus that inserts its genome into the DNA of a person’s immune cells, specifically their T cells and macrophages. Latent hepatitis C virus resides in the liver.
Over the past 20-30 years laboratory measurements have become sensitive enough to pick up on viral RNA outside the known sanctuary locations.1
“We were surprised to find that this was common in measles—its main site of persistence is lymphoid tissue,” says Diane Griffin, a microbiologist and immunologist at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. “Anybody who looks will now find RNA persistent, probably, after acute virus infection.” Such signs have been found in blood, joints, the respiratory tract, gastrointestinal tissues, and kidneys.
Some viruses can remove external signs that a cell is infected, allowing them to escape the attention of the immune system in places outside conventional sanctuary sites.
What do they do there?
Whole viruses, also called virions, comprise either RNA or DNA surrounded by a protein coat. Those that persist in sanctuary sites can continue gradually infecting the cells around them. There they hijack the host cell(s) to make copies of themselves.
How long can viruses hide for?
It varies. Griffin’s team has also found measles RNA months later than it was previously recognised, after the infectious virus has been cleared.7
A low level of immune activity in sanctuary sites usually keeps the viruses under control without killing the cells. And sometimes—especially outside sanctuary sites—the immune system can clear the virus but leave its genetic material behind to reproduce later, known as a “latent” virus.8 For example, antibodies in the brain may suppress viral RNA production without harming infected neurons.9
There are more than a dozen viruses that can become latent, of which Epstein-Barr virus is one of the most common, infecting as much as 90% of the human population.10 After an initial Epstein-Barr infection, the remaining viral RNA can lead to later disease and asymptomatic viral shedding.
Other latent viruses include DNA herpesviruses,11 varicella (chickenpox), and herpes simplex viruses. Chickenpox is well known for reactivating to cause shingles, and herpes simplex can give rise to mucosal ulcers and cold sores, which help the viruses to infect a new group of susceptible people.
Transmission can take place months or even years after recovery from acute disease, potentially enabling spread to new geographical regions. As one potential example, in 2021 in Guinea, an Ebola survivor had a recurrence of acute illness one year after their initial infection.12 This led to community infection and triggered a “new” outbreak. This, says Griffin, is an example of evolving understanding about what persistence means in Ebola and the potential public health and long term consequences.
She also points out that some viruses such as Ebola and Zika don’t have a known latent phase, yet “we know people where, six months after recovery, you get transmission of Zika, or Ebola, or reactivation of problems . . . That means that full length RNA is there and can resume production.”
Can different variants hide for longer?
Sometimes. Viruses often evolve so that they avoid inducing innate immune responses,13 helping them replicate and survive longer inside cells.14 These are variants that are less likely to burst cells open, or that can limit or prevent the expression of proteins that make them recognisable by antibodies, or both.
Griffin notes that such variants may not be so readily transmitted. She highlights the fatal brain infection subacute sclerosing panencephalitis, which occurs seven to 10 years after a measles infection.15 “That virus is highly mutated by that time,” she says. “There is a good immune response, but the immune response does no good. It’s not capable of getting rid of those cells.”
With SARS-CoV-2, Daniel Chertow, a critical care and infectious disease specialist at the US National Institutes of Health Clinical Center in Bethesda, Maryland, has found differences depending on where the virus is found. From autopsy samples, his team sequenced the genetic code for the SARS-CoV-2 spike protein that helps the virus enter cells. Usually, explains Chertow, what you find in the lungs is more or less what you find elsewhere, but this wasn’t always the case. “There was a variant in the brain that was distinct from what we found in the respiratory tract,” he says. “That is suggestive that this virus has the potential to ‘evolve’ in different anatomic compartments.”
Where does SARS-CoV-2 hide?
This is still being investigated. One study describes autopsies that found traces of SARS-CoV-2 RNA in the lymph nodes, small intestine, adrenal gland, heart, and brain, persisting for 230 days after symptom onset in one case.16 For comparison, in another paper, an immunocompromised 4 year old boy secreted influenza virus in his stool for over two months after infection but for over 18 months in his respiratory secretions.17
“Previously the paradigm was that this was predominantly a respiratory virus,” says Chertow, who led the study. “At least in a subset, this has the potential to be a widely systemic virus that can infect cells and tissues throughout the body, including in the brain. It also has the potential to replicate in those different sites.”
Does viral persistence cause long covid?
Some studies have associated persistent SARS-CoV-2 RNA with long covid, known technically as post-acute sequelae of covid-19 (PASC), although others have not.18 Studies have also found viral RNA in the blood of people with more severe covid-19, suggesting that infection has spread systemically, and this is one of a number of factors that might help predict PASC.19 However, it’s not yet clear how important this viral RNA is when compared with inflammation, autoimmunity, or the possibility that SARS-CoV-2 has reactivated latent infections with other viruses such as Epstein-Barr.
Griffin says it’s likely that long covid is actually more than one disease, with multiple contributing factors. You can almost always find viral RNA in acute covid-19, she says, but only a few people have any long term consequence of that—which is “one of the puzzling features.” Yet she believes that the link between viral RNA and long covid is “likely to be very important.”
Chertow adds, “Among the different hypotheses about what underlying drivers of the clinical manifestations of long covid might be, [viral] persistence is high on that list.”
What about other postviral syndromes?
Various viruses, including parvovirus B19 and Epstein-Barr, have been linked to triggering myalgic encephalomyelitis (chronic fatigue syndrome or ME/CFS).20 However, as with long covid, Griffin says that “there may likely be more than one different kind of infection that can lead to that particular syndrome.”
It’s hard to disentangle connections with persistent viruses. “We have a big advantage with long covid in that we have a much better understanding of the virus and we have a lot of people to study,” she says. “We can hope that all that attention will result in a better understanding that can be applied to these other syndromes.”
Another positive development is the spotlight now being shone on virus reservoirs because of the pandemic. “This has not been an area that has received much attention until now,” says Griffin. In her opinion, research into SARS-CoV-2 is likely to teach humanity about older viruses, particularly the role of persistent RNA.
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Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.
Provenance and peer review: Commissioned, externally peer reviewed.
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