Why Epstein-Barr is the ‘everything virus’
Virtually all of us have been infected, but an unlucky few develop lifelong illness
Illustration by Marta Spendowska
When Rae Mainwaring was 13, she developed a peculiar illness. She recalls “just feeling awful” and experiencing a crushing fatigue. “I remember it being hard to put my finger on what it was,” she says. “It felt like a really horrible flu, but it just didn’t get better.” She missed six months of school in Birmingham, England, and attended part time for another six months.
A few weeks in, Mainwaring’s doctor diagnosed her with infectious mononucleosis, or mono. It is most commonly diagnosed in teenagers and young adults and is known as “kissing disease” because it spreads through saliva. Typical symptoms include a high fever, sore throat and swollen lymph nodes. For Mainwaring, the isolation dragged. “Back in the early ’90s, it was hard to keep in touch with people if you were not in school,” she says.
Once the year-long fatigue eased, Mainwaring got on with her life and went to university. Almost a decade later, though, she began to experience numbness in her face. Her doctor said it was probably a migraine, but that she should get an MRI anyway. While waiting for the results, Mainwaring graduated, moved away, got a job doing costumes in theater and forgot about the MRI. She worked hard and partied hard, and she attributed any weird symptoms to “burning the candle at both ends.”
Then, about a year later, the numbness returned, no longer confined to her face. “I was struggling to do buttons up, dropping keys, my ankles kept [giving out],” Mainwaring says.
When she went back to the doctor, Mainwaring, then 24, learned she had missed her MRI results because they had been mailed to her old address. The brain scan revealed that she had multiple sclerosis, a neurodegenerative disease in which the body’s immune system attacks the protective myelin sheaths around neurons. Depending on which parts of the nervous system are affected, patients can experience a range of symptoms, from numbness and fatigue to muscle spasms, difficulty walking, memory problems and vision loss.
Learning she was really ill, just when her life was getting going, was a big shock. “Suddenly you’re having to sleep all the time, having to say no to friends and say no to things, and having to step back from the world,” Mainwaring says. It reminded her of being sick with mono.
That feeling was no coincidence. Scientists now know that Mainwaring’s mono and MS are both caused by the same infectious agent: the Epstein-Barr virus. This driver of illness is also linked to autoimmune diseases including lupus and Sjögren’s syndrome. It also causes roughly 2 percent of all cancers globally; nearly 360,000 new cases and up to 210,000 deaths per year. There is also growing evidence that EBV lies in wait and springs back into action in some patients with long COVID, contributing to their symptoms.
But the strangest thing about the virus is this: Some 95 percent of us are infected. In most people, it never causes disease, but in others, it overturns their lives. There are no antivirals or approved vaccines for EBV, though some companies are currently testing candidates. And because EBV is a master at tricking the immune system, it is difficult to eradicate it from a person’s body.
“EBV has developed to evade and escape the immune system at every juncture, because that’s how it survives,” says rheumatologist William Robinson of Stanford University.
Robinson is one of many scientists working to understand how the virus works. His research, and that of other scientists, has revealed that EBV infects key immune cells to rewire the immune system to its own advantage. There is also evidence that the virus can mimic some of the proteins in our bodies, leading to immune system attacks on healthy cells expressing those proteins.
Understanding how EBV works “could offer real hope for future treatment and prevention,” says Catherine Godbold, senior research communications manager at the MS Society in the United Kingdom. “It’s exciting to see the momentum building in EBV research, and we look forward to seeing where it leads.”
Accidental discoveries
Like a lot of things in science, our knowledge of EBV came about thanks to a series of accidents. In 1964, pathologists Michael Anthony Epstein and Bert Achong, along with virologist Yvonne Barr, were trying to find out why a pediatric cancer called Burkitt’s lymphoma was so aggressive. In cells grown from samples from Ugandan children with the cancer, they spotted particles of a virus, soon dubbed Epstein-Barr. It was the first known cancer-causing, or oncogenic, virus.
Four years later, another group of scientists at the University of Pennsylvania linked EBV to mono after lab technician Elaine Hutkin fell ill with the disease.
Virologists at the lab, led by Gertrude and Werner Henle, wanted to know how the virus was transmitted and what it did to human cells. So they put infection-fighting white blood cells called lymphocytes into dishes containing EBV and recorded whether the cells lived or died. Many of those cells came from Hutkin. Before her illness, none of her lymphocytes survived. But after her infection, they grew in the presence of EBV — and her blood contained antibodies against the virus.
Intrigued, the Henles performed similar before-and-after tests with lymphocytes from other individuals who had mono, demonstrating that EBV is the main infectious agent behind the disease.
Just like that, within a decade, EBV had been revealed to cause both an aggressive cancer and a debilitating infection.
EBV is a type of herpesvirus, which replicates by writing its DNA into the nuclei of infected cells. Nine herpesviruses infect humans, including the viruses responsible for oral and genital herpes and the varicella zoster virus, which causes chickenpox and shingles. Like other herpesviruses, EBV latches onto us for life.
Once EBV enters the mouth via saliva, it infects the cells lining the back of the throat. From there, it makes its way to white blood cells, showing a preference for one particular subset: the B cells that help the body learn about new pathogens. Using a protein called EBNA1, viral DNA attaches itself to the B cell’s chromosomes. When the host cell divides, it makes copies of the viral DNA as well, allowing the virus to slowly spread.
EBV may remain latent in our B cells for years, but it isn’t entirely inactive. “It’s tweaking cellular pathways that cause the cell to stay alive longer than it should,” says viral oncologist Blossom Damania of the University of North Carolina at Chapel Hill. It also causes the cell to multiply longer than it should, which can lead to cancer.
Damania’s team is working to develop a steroid called Withaferin A, which can kill EBV-associated non-Hodgkin lymphomas in the lab. Ultimately, the team wants to see if the steroid can be used in humans when typical chemotherapy and immunotherapy approaches fail.
Long-term impacts
The cancer link may no longer be a mystery, but the connection to MS is a different story.
It’s a puzzle that Alberto Ascherio, an epidemiologist at Harvard University, has devoted 30 years to solving. Some of his earliest studies identified risk factors for MS, such as smoking. But he was obsessed with finding the root cause of the condition.
From the start, Ascherio suspected EBV. He knew that mono is caused by EBV, and that people who have had it, like Mainwaring, are at greater risk of MS. He also knew that people who have never had EBV seemed to be at low risk of MS. But he spent 20 years struggling to provide definitive evidence.
The problem with demonstrating the relationship between EBV and MS is both simple and enormous: EBV is simply too common. By the age of 20, most people have already been infected with the virus, Ascherio says. About 95 percent of adults have antibodies against EBV, even if they have never had symptoms. And whereas EBV is ubiquitous, MS is far less common. The global prevalence is thought to be 0.024 percent, or approximately one in every 4,200 people.
“Everybody in the field [was] like, come on, it can’t be. Everybody has EBV. How could it cause autoimmunity?” Robinson says.
Demonstrating that link would require a truly huge study, one with enough people who had never had EBV, yet also with enough people who had been diagnosed with MS.
Ascherio and colleagues finally pulled this off in 2022 using samples from members of the United States military, which regularly screens its troops for HIV. Blood samples from over 10 million personnel on active duty between 1993 and 2013 revealed that 5.3 percent were EBV-negative when first tested.
When researchers examined the 801 samples of people diagnosed with MS, they found that all but one had EBV antibodies. Compared to the uninfected population, that meant EBV increased the risk of MS by a factor of 32. “It really showed that if you could prevent the viral infection, you could prevent the disease,” Ascherio says.
Attacking the brain
Even as we learn more about EBV, a big mystery remains. How could the same virus cause no symptoms in most people, debilitating infections in some and cancer or autoimmune disorders in others?
The answer lies not in the virus but in our own immune systems, Ascherio says. “The immune response to the virus is what determines whether you get the disease or not.”
There are two main ideas about how this plays out, and both turn on EBV’s habit of infecting B cells.
One possibility is that EBV mimics other proteins found in the human body, setting the stage for an immunological case of mistaken identity. Robinson and his team found that out, again, by accident.
A decade ago, a postdoc in Robinson’s lab was studying antibodies from the blood of people with MS, trying to figure out which proteins they erroneously latched onto. Because MS is a neurological disorder, the postdoc assumed that the antibodies would bind to proteins from the brain. No luck. But when the postdoc exposed the antibodies to an array of viruses, they bound to EBV.
“It hit us in the face. It was just such a striking finding,” Robinson says. By 2022, the team had shown that the EBNA1 protein, which the virus uses to latch onto B cell chromosomes, is exceptionally similar in structure to a human protein called glial cellular adhesion molecule, which helps some liver and brain cells stick together and communicate.
This molecular mimicry may help explain why EBV causes MS. If EBV’s proteins resemble those found in the human brain, the immune system might mistake the brain proteins for the viral ones — and launch an attack.
Researchers have since found that EBNA1 mimics two brain proteins: anoctamin-2, which is involved in signaling, and alpha-B crystallin, a repair protein. In 2025, Robinson’s team found that, compared to healthy individuals, patients with MS show stronger antibody responses to all of these proteins, hinting that their immune systems are attacking the healthy brain cells that express them. Further studies suggest EBNA1 can be found in the B cells, neurons and glial cells of MS patients — indicating that EBV infects all these cells.
The other possibility is that the infected B cells themselves are the culprits. Each of us has millions of B cells, some of which are autoreactive, or predisposed to attack our own tissues. In healthy people, autoreactive B cells are suppressed and harmless. But Robinson’s team has found that when EBV infects this subset of B cells, it turns them against the body.
In a yet-to-be peer-reviewed study released in February, Robinson’s team found EBV in B cells in the blood and cerebrospinal fluid of people with MS. Once infected, the B cells began behaving differently. These immune system “commanders,” as Robinson calls them, started activating other white blood cells, including T cells. The T cells are the “ground troops” that eventually attack the central nervous system, he says.
And in a paper published in July in Science Translational Medicine, researchers affiliated with the U.S. military study identified specific subsets of the “ground troops” that likely launch this attack.
“It’s very nice now to be able to understand more about the underlying mechanisms of how EBV likely causes MS,” says study coauthor Kjetil Bjornevik, an epidemiologist at Harvard University. Bjornevik says he hopes the findings will be a step in the right direction to find new treatments for MS patients and those most at risk of developing the disease.
Genetics may help determine who is most at risk. In another study, researchers looked at the health records and genomes of more than 735,000 people in the United States and the United Kingdom. Some people had high levels of EBV DNA in their blood, indicating that their immune systems hadn’t successfully cleared the virus. The team then identified 22 regions of the genome, many containing immune-related genes, that were associated with these higher levels.
In a different yet-to-be peer-reviewed paper, scientists expanded the list of regions in the human genome associated with severe EBV infection and MS risk to 39. That study also found that B cells infected with EBV behaved oddly, overexpressing genes known to be associated with a higher risk of MS. The infected B cells had also activated signaling pathways that turn on T cells, the “ground troops” that trigger MS by entering the brain and attacking neurons.
While the details of the mechanisms remain to be worked out, the big picture is increasingly clear. For people whose immune systems cannot handle EBV, the virus “has its run of the house,” Robinson says. “It can reactivate at will, and it’s not fully controlled.” Reactivation of EBV may help explain why people like Mainwaring experience unpredictable changes in their MS symptoms.
There is a lot left to unpack about the connection between EBV and MS, but Ascherio says the virus is the primary cause of the disease. “Some people are still puzzled by the fact that most people infected with EBV don’t get MS,” he says. “I am puzzled that they are puzzled.”
Fighting back
For all that science has learned about EBV, no one has come up with a good way to fight the virus, Robinson says. Some antiviral medications, for example, display mild activity against EBV, but none are effective. And there is no approved vaccine.
Some of the most effective treatments for MS on the market are monoclonal antibodies that target specific molecules found in B cells. They can reduce relapse rates and slow the progression of disability, but they don’t target the EBV at the root of the condition.
On the antiviral front, one promising option is tenofovir alafenamide fumarate, which is used to prevent HIV from replicating and causing infection. Studies suggest the drug can do the same to EBV. Ascherio is involved with a randomized controlled trial testing whether the drug can control EBV in people with a type of MS that periodically flares and remits. He calls it “the most promising” antiviral to date, especially since it is already known to be safe.
On the vaccine front, there are a handful of candidates — and many more failed attempts. One promising vaccine, dubbed recombinant gp350, made it to clinical trials in the 2000s. Although it reduced the risk of mono, it could not prevent infection.
One major problem for vaccine developers is that EBV is relatively complex compared to other viruses. It contains around 100 genes whereas SARS-CoV-2, the virus that causes COVID-19, contains just 11. The influenza A virus, meanwhile, has eight genes. EBV’s large array of genes means the virus can make multiple proteins to enter human cells. Blocking just one isn’t enough, Damania says.
That’s why vaccine makers are taking aim at several EBV proteins at once. Pharmaceutical company Moderna, for example, has two EBV candidate vaccines in the pipeline. One is a prophylactic vaccine, which aims to reduce rates of mono and perhaps prevent EBV infection. It targets five EBV proteins, with the goal of preventing the virus from infecting respiratory tract lining cells or B cells.
“If you prevent EBV infection, then all EBV-related diseases are gone,” Ascherio says. “That is the holy grail.”
The other is a therapeutic vaccine that targets additional EBV proteins. It is given after infection, in the hopes of reducing a person’s risk of developing MS.
Clinical trials of both approaches are underway. Trials to test safety and efficacy of the prophylactic vaccine in healthy 10- to 30-year-olds are expected to conclude in October. Meanwhile, the therapeutic vaccine is undergoing an efficacy trial in people ages 18 to 55 with multiple sclerosis; it is due to finish in 2029.
Mainwaring, now 46, is eager for a vaccine, not only for herself but also for her two teenagers, ages 13 and 15. She worries “constantly” about them contracting EBV — and developing the cascade of other conditions that could follow.
She still has symptoms such as fatigue and numbness nearly every day, and she lives with the possibility that her MS could lead to an irreversible decline. Every few years, she experiences a relapse in which her symptoms become dramatically worse. At that point, her doctors give her a massive dose of steroids to bring the condition back under control. “It’s constantly changing and evolving,” she says. “You sort of have to learn to make peace with that.”
