There's a good chance you have a virus called CMV. It might seem to have no effect – or it might be life-changing.
PHOENIX – Long before the coronavirus pandemic, Kathleen Muldoon knew what it felt like to have her life changed by a virus.
In 2013, Muldoon was teaching embryology at the Geisel School of Medicine at Dartmouth. She was also pregnant with her second child.
It was a fact that she shared openly with her medical students. She was set to have the baby around the end of the semester, and as she taught them each stage of development, she could give them real-life examples from her own pregnancy.
But at 20 weeks, Muldoon’s doctors saw something on the ultrasound. It might not mean anything was wrong, they said, but they wanted to screen her for TORCH infections, a set of congenital infections that can be transmitted during a pregnancy, delivery or after birth. Often, those infections are mild or don’t cause any symptoms at all. But in some cases, they can cause the baby to experience birth defects and in some cases lifelong disabilities or impairments, including vision and hearing loss, seizures and cognitive and motor impairments.
Viral facts
• Latent viruses like CMV end up infecting most of us, yet most people have no or few obvious symptoms, while a small percentage of people face catastrophic ones.
• COVID gives science new urgency to figure out why there’s such a difference.
• Viruses have an inherent ability to unlock our immune systems, but scientists are gaining new insights into the mechanisms they use to hijack our own cellular processes. Studying them can give researchers clues to better understand, and eventually even strengthen, our immune systems.
• Imminent advances in virology, immunology and vaccine development may help us find ways to prevent the viral infections – like CMV – that lead to severe effects for some.
The C in TORCH stands for CMV – cytomegalovirus, a type of herpesvirus that infects between 50% and 85% of adults in the U.S. and almost all adults in other parts of the world. Most of us never realize we have it, but a pregnant person who has an active infection with CMV can pass it on to the baby.
When the doctors screened Muldoon, they found that her immune system had produced antibodies against CMV. Muldoon, who had never given much thought to antibodies, her immune system or the prospect of a latent virus, worried for her future child.
“I didn't know anything about these things at that time,” she said. “In the meantime, I had gone to Dr. Google and looked at CMV and been scared out of my mind.”
The doctors said the antibodies could have just been the result of a prior infection – they didn’t necessarily mean her body was actively fighting the virus. So for a while, Muldoon felt comforted. Her baby would be all right.
“I went about the rest of my pregnancy happy as a lark,” she said. “It was amazing.”
But when Muldoon’s son Gideon Dobson was born, the OB mentioned to the nurses that the baby looked a bit jaundiced. The OB told them to put him under the lights. And that’s when the symptoms started appearing: a telltale rash, a bloated stomach. Then the doctor came in.
“I remember (the doctor) washing his hands and not making eye contact. And eventually he turned to us and he said, ‘I don't know what to tell you. I think it's CMV,’” Muldoon said. “It was like there was a crack in the planet.”
The nurses took Gideon to the NICU at Dartmouth, where Muldoon had been teaching for six years.
“We shuffled out into the winter night, behind the ambulance, and spent the next six weeks in the NICU acclimating to our new life,” she said. That was only the beginning. Soon after, Muldoon and her family decided to move to Arizona, where there was less snow and better disability care.
Now, Gideon is 8. He has 36 diagnoses and sees 17 specialists. He lost his hearing when he was three, a common result of a CMV infection, and wears a cochlear implant. But Muldoon said that while Gideon has a disability, he isn’t sick. He attends school at the Foundation for Blind Children, which provides education for kids with special sensory considerations. His mom says he loves music and bright colors.
“There’s nothing I would change about (Gideon) at this point in our journey,” Muldoon said.
But she also hopes that one day a shot could prevent other kids from catching the disease.
“We wish there was a CMV vaccine,” she said.
Scientists and drug makers have been seriously investigating a potential CMV vaccine for years. The concern is particularly serious for pregnant people, as well as for those undergoing transplants (CMV infections can be deadly in immunocompromised people).
Moderna was able to create an mRNA vaccine against SARS-CoV-2 so quickly in part because they had already been working on a CMV vaccine using the same technology for several years. Their CMV vaccine is now in Phase III clinical trials.
For families like Muldoon’s, the effects of CMV are obvious. However, millions of other people contract CMV, often asymptomatically and in childhood, with apparently no consequence. The researchers who study CMV are still trying to unravel the potential costs and benefits of carrying such invisible hitchhikers for our entire lives, but they don’t just see viruses as potentially delivering disease. They see them as tools to better understand our immune systems.
Researchers say that understanding is more urgent than ever – not just because the novel coronavirus poses so many threats to our immunity, but also because the insights virus research yields in the short term could one day help us develop a new generation of vaccines.
Those vaccines wouldn’t just target the immediate effects of latent viruses. Some researchers suspect that, because latent viral infections can affect the long-term abilities of the immune system to keep the body’s cells running smoothly, preventing those infections could also prevent more complicated health issues like cancers that happen decades later. That’s why many aspects of cutting-edge cancer research hinge on advances in immunology and virology.
But before we get there, scientists first have to understand why so many people are infected with latent viruses and yet only a few experience any symptoms at all.
The CMV conundrum
It’s a puzzle Felicia Goodrum has wanted to solve for a long time. A professor of immunobiology at the University of Arizona who studies interactions between viruses and their hosts, Goodrum is interested in connections between latent viruses and chronic disease, and specializes in CMV.
“Why does one person get (cancer) and the other person doesn't? Why do some people have a herpes simplex infection that reactivates all the time and other people don't ever get reactivation? And what are those differences? I think ultimately, that's what we all kind of want to understand,” she said.
Goodrum says she came to appreciate the power and potential of viruses while she was still in graduate school.
“The first cancer-causing genes were discovered ... because viruses were modulating those genes,” Goodrum said. “It’s one of the most beautiful examples of viruses teaching us.”
Now, decades later, she and her team are discovering that CMV may be using tools from host cells for its own benefit.
“It's always been presumed that a virus like cytomegalovirus doesn't really need a lot of the host cell,” Goodrum said. But now, she and her team have realized that isn’t true.
In a study that has not yet been published, Goodrum said they observed CMV manipulating proteins in the host cell called polymerases. If DNA is like a zipper with its two intertwining strands, then polymerases are like the zipper pull that moves along them. They perform vital functions that allow the body to read and repair its own DNA.
As CMV meddles in those processes for its own ends, it could be disrupting our body’s ability to repair its own DNA as it interacts with our cells over decades. When we lose the stability of our own genome, “that’s when cancer occurs,” Goodrum said. The advances her team is making point to future directions for research on cancer, aging and longevity.
However, previous research in mice has also shown that CMV infections may actually lead to more robust immune responses to other infections later in life. In a 2018 study, University of Arizona researchers showed that older mice who had been previously infected with CMV mounted better immune responses to listeria (a bacterium that, in humans, causes stomach flu, among other problems) than those that had not had CMV. They hypothesized that CMV was somehow sending a signal to the immune system to marshall the troops, meaning better defenses against disease overall.
Still, Goodrum emphasized that for humans, “we don’t know what the costs and benefits may be of carrying CMV your entire life.” Though CMV may provide some marginal benefit to some individuals, those without CMV don’t see any detriment – they are just as healthy as those with CMV. Meanwhile, a lurking CMV infection may have connections to frailty in aging and heart disease, among other health issues.
The problem, Goodrum said, is that it’s difficult to design controlled clinical studies because so many people are infected with these viruses – it’s hard to gather a control group that hasn’t been infected. So for now, she and other researchers are trying to understand the basic mechanisms of how these viruses work, in an attempt to better understand their relationships with our cells.
“Viruses know our biology better than we do,” Goodrum said.
Herpes, a sneaky virus
One of Goodrum’s old friends from undergrad agrees. Greg Smith, now a herpes researcher at Northwestern, is working on another part of the mystery of latent viruses – how herpesviruses get into the nervous system.
Unlike a virus like rabies, which requires the physical damage of, say, an animal bite to get into the nerve endings and eventually the brain, herpes gets into the brain another way. If you get infected as a kid when a grandparent gives you a hug or kiss, the virus has a long way to travel from the nose or mouth all the way to the nervous system.
It does that by taking advantage of our own cells. Like a train along a track, herpes rides down tiny fibers in our nerve endings. Then it gets to a central station in the neuron called a centrosome, a stop on the way to its end destination, the nucleus.
The story should stop there, because the virus needs a special key to move past the centrosome. But that’s where Smith made his discovery: herpes is so specialized to get into our nervous system that it knows how to steal the key ahead of time. When it first enters the membranes that line the nose and mouth, it snatches up one of our own cellular proteins that it can later use in the neural centrosome.
Smith sees this as a prime example of the potential insights to be gained from studying latent viruses like herpes. Knowing about this viral strategy could give scientists a leg up in developing new vaccines. For example, if scientists found a way to disarm herpes from grabbing its protein “key” before it gets to the nervous system, they could give people a more innocuous version of herpes that can’t deliver their genetic material into neural cells. Or they could develop vaccines that target virus actions in specific parts of the body, such as mucous membranes.
While Smith acknowledged that many virologists would be skeptical about the idea of eradicating herpes, one of our oldest and most universal viral companions, he believes there is much to be learned – and gained – from better understanding them.
“Pathogens are the greatest scientists,” he said. “It’s amazing what things we could learn if we knew how herpes does what it does.”
HTLV-1: How a virus turns T-cells cancerous
To find out more about the mechanisms of viruses, and by extension, the mechanics of our own immune cells, researchers have rapidly advanced new technologies.
Masahiro Ono, a T-cell expert and immunologist at Imperial College London, described the growing popularity of a revolutionary technique called single-cell RNA sequencing, which allows scientists to analyze how individual cells look and act differently from one another.
Ono and his team, along with his co-author Yorifumi Satou and other collaborators in Japan, recently used this technique to study another latent virus called HTLV-1, which is endemic to parts of Japan and other countries including some in Central and South America and Africa. Much like other latent viruses, HTLV-1 can infect wide swaths of people – experts estimate that at least 5-10 million people are currently infected – but many of those infections appear to be asymptomatic. However, in a small percentage of those people, HTLV-1 can contribute to more serious disease, including a type of leukemia called ATL, which affects the T-cells.
If you’re familiar with T-cells, it might be because they're often mentioned in reference to vaccines against COVID-19. Immunologists have been hopeful that T-cells can help provide a more durable response to a coronavirus infection, even long after our antibody levels drop. That’s because while B-cells and their antibodies try to stop the coronavirus from entering our body’s cells, T-cells can detect which cells have already been infected and destroy them, and their ability to do that doesn’t seem to wane as much over time.
Ono and his team recently discovered that HTLV-1 “sleeps” in the genome of T-cells, as he puts it. But occasionally it wakes up and produces more virus particles that infect other T-cells, then goes back to sleep. A lifelong relationship with the HTLV-1 virus can eventually cause infected T-cells to become overactivated, making them more susceptible to environmental factors that can cause them to become cancerous.
Like researchers studying herpesviruses, Ono was surprised to find that HTLV-1 was taking advantage of host cell machinery. But he hopes if they can understand exactly how the process of T-cell overactivation works, they can one day find a way to control infected T-cells, making them less likely to “misbehave” and cause leukemia.
He credits single-cell RNA sequencing for the advancements they have already made. “We can understand how infected T-cells change into cancer cells in an unprecedented way,” Ono said.
But he also added that there are plenty more outstanding scientific problems to be solved in the T-cell field, and that compared with B-cells and antibodies, we still have relatively limited methods to analyze T-cells. “We still need to do basic research to understand how T-cells recognize and memorize the target, the pathogen and how they maintain immunological memory,” he said.
And he added that his same basic research that could one day help us better understand and prevent leukemia could also help us right now, as we grapple with the COVID-19 pandemic. He described feeling a sense of greater responsibility to communicate about the importance of T-cells as more people learn about vaccines, viruses and immunity.
“Before the pandemic, every immunologist knew that T-cells were important, but that was not relating directly to everybody’s life,” Ono said. “(Understanding T-cells) is critical because in this pandemic, we hope that our immunity will be robust enough for any future variants.”
Protecting the vulnerable
Nearly two years into the COVID-19 pandemic, Muldoon is well aware of the need for public health measures, education and awareness to keep vulnerable populations safe. She described the challenges of caring for Gideon alongside his two siblings while managing Zoom school and working from home.
“We’re very COVID conscious, we're very, at times, afraid, and really mitigating all of our exposures,” she said. “We really haven't left our bubble since March 2020.”
But the pandemic hasn’t stopped her from continuing to advocate for families of children with CMV and providing information for expecting parents. Now, in addition to her position as an associate professor at Midwestern University’s medical school in Glendale, Arizona,, Muldoon is the chair of the scientific advisory committee at the National CMV Foundation and hopes to raise awareness about the virus. While she would love to see a CMV vaccine come to fruition, in the meantime she is working on education and outreach.
Like COVID-19, CMV “has a heavier burden in like historically excluded and underrepresented communities,” Muldoon said. “One of our main goals, especially in Arizona, with our population being super young and really heavy in Latino communities, (is) that we are (building) an entire website in Spanish.”
She encouraged pregnant people to practice good hygiene and protect themselves from viruses, including SARS-CoV-2, that can impact the health of their babies.
“Most kids are not Gideon, but when you’ve been on the other side of those stats, you’re not willing to roll those dice again,” Muldoon said.
MORE IN THIS SERIES
How latent viruses live inside your body, and what COVID-19 is teaching us
Studying space travel may help scientists learn more about the immune system, long COVID
Follow reporter Melina Walling on Twitter @MelinaWalling.
Independent coverage of bioscience in Arizona is supported by a grant from the Flinn Foundation.
This article originally appeared on Arizona Republic: CMV and herpes are latent viruses that could help create new vaccines
