A new view into viruses in the body

Some viruses make us sick and are cleared within days by the immune system, but other viruses lurk in our bodies for a lifetime and can re-emerge later to cause new problems. How and why viral levels change in the body over time — and the health impacts of these changes — are only just starting to become clear.

In a new paper published in Nature, scientists from the Broad Institute, Mass General Brigham, and Harvard Medical School report the largest analysis to date of the human DNA virome — the collection of viruses in the body that have DNA as their genetic material. 

By analyzing data from over 900,000 individuals from three biobanks, the team tracked the amount of virus particles — called viral load — in blood and saliva for several common DNA viruses, including Epstein-Barr virus, which can cause an infection called mononucleosis and is a risk factor for multiple sclerosis and certain cancers later in life.

The researchers saw large variations in viral load from person to person depending on age, sex, and even season of sample collection and lifestyle. They also discovered dozens of genetic factors strongly associated with viral load, as well as intriguing patterns, such as a higher viral load in men than in women for all seven of the viruses they analyzed in detail. Overall, the authors found that genetics plays a role in determining whether the effects of these viruses — particularly Epstein-Barr virus— extend well beyond an initial infection.  

“We're getting to the point now where we can use human genetics to try to answer fundamental questions about pathology resulting from viruses,” said lead author Nolan Kamitaki, a graduate student at Broad and Harvard Medical School. “This kind of research can tell us, for example, whether a virus is likely to have a role to play in causing cancer or another disease later in life.”

Kamitaki recently conducted a study looking into how genetics shapes the oral microbiome, using similar methods to unlock information hidden in vast amounts of DNA data.

“My lab is broadly interested in what we can mine from genomic data that’s readily available to researchers. We’re finding that population sequencing datasets capture information about not only the genomes we inherit, but also the oral microbiome, these hidden viruses, and acquired mutations—and we can sometimes link these to downstream health consequences,” said study senior author Po-Ru Loh, associate member at the Broad and associate professor of medicine at Harvard Medical School and Brigham and Women's Hospital.

Viral variations

The scientists analyzed whole genome sequencing data from participants from the UK Biobank, the All of Us Research Program, and another dataset called SPARK, homing in on viral DNA from blood and saliva samples. In addition to the Epstein-Barr virus, they studied two other human herpesviruses(HHV-6 and HHV-7), Merkel cell polyomavirus, and three anelloviruses, which are found in about 90 percent of all people.

The team’s analysis revealed that each virus had markedly different trajectories over a lifetime. The viruses appeared most rapidly during the first several years of life, likely after primary infection, but the prevalence of Epstein-Barr virus continued to increase with age, while HHV-6 decreased after childhood, possibly indicating more control by the immune system over time. HHV-7 similarly decreased sharply in middle age.

The scientists also found that Epstein-Barr DNA went up in the winter, and down in the summer, but found the opposite for HHV-7. Similarly, smoking was strongly associated with increased Epstein-Barr DNA — nearly twice as high for heavy smokers compared to nonsmokers. But, for HHV-7, smoking was associated with decreased prevalence. Across all seven viruses though, the researchers saw that men consistently had more viral DNA in both blood and saliva than women did.

Many of the genetic factors most strongly linked to viral load were related to how the immune system responds to viruses and how infected cells are able to dodge immune attack. These findings highlight how important the immune system is for controlling the amounts of viruses hiding in the body and how much immune responses can vary over time and between people.

“It’s amazing how much DNA can teach us about dynamic biological processes and the ways in which our habits, our genes, and our biology shape those processes,” said study author Steve McCarroll, Broad Institute member and director of genomic neurobiology for the Broad’s Stanley Center for Psychiatric Research.

Epstein-Barr effect

The largest number of genetic associations the scientists found were centered around the Epstein-Barr virus, so the team dug a little deeper. Their analysis revealed that the lifetime Epstein-Barr viral load didn’t influence the risk of developing multiple sclerosis — rather, the immune response to the virus is likely how the virus raises the risk of the disease.

The team found evidence, however, that high Epstein-Barr viral load is a causal risk factor for Hodgkin lymphoma — a finding that they say needs further study in cell and animal models in the lab.

“This finding is particularly interesting to me, and is an example of why virus research in large genetic biobanks is important: it allows us to begin answering questions about whether a virus like Epstein-Barr is a causal factor in disease and cancer,” said Kamitaki.