Rethinking an old viral foe

Why does a common virus plague bone marrow transplant patients? New study challenges dogma, opens door to new therapies.
illustration of antibodies specific for individual CMV strains
Y-shaped antibodies specific for individual CMV strains (depicted by same color) can prevent the virus from reactivating after transplantation. Other CMV strains (depicted in black) can escape. Image courtesy of Dr. Mariapia Degli-Esposti, Lions Eye Institute, Perth, Western Australia

You may not have heard of cytomegalovirus, but the two of you have likely met.

In fact, odds are it’s dozing inside you right now.

Cytomegalovirus, or CMV, infects at least half of all adults worldwide. Most are unaware they’re infected because their healthy immune system keeps it in check. The virus slips into dormancy, becoming a passive and lifelong passenger.

But CMV can roar back to life in anyone with a compromised immune system. The results can be life-threatening, and the virus has plagued bone marrow transplant patients for decades.

A new study in Science may rewrite the story of why the virus wreaks such havoc — and hint at how to stop it.

The research challenges long-held theories about how the body controls CMV. The twist: The immune system’s defense against CMV isn’t a solo performance. After years of studying a mouse model, a team of researchers led by Dr. Geoffrey Hill shows that an unsung actor — antibodies — plays a vital role.

Antibodies are one of the body’s chief ways of defending itself against infection. These Y-shaped proteins can bind, like a lock and key, to bad actors and neutralize them. 

Hill’s insight could pave the way for cheaper, safer therapies using antibodies to protect transplant patients against CMV. In a tantalizing hint, the researchers found that a dose of the right antibodies after transplantation can keep the virus dormant in mice, without the need for any other immune cells.

“This is a big deal for the transplant field,” said Hill, the study’s senior author and director of Hematopoietic Stem Cell Transplantation at Fred Hutchinson Cancer Research Center. “We’re turning dogma on its head, and that could meet the urgent need for inexpensive and nontoxic therapies to improve patient outcomes.”

‘The data are the data’

First, the dogma.

Conventional wisdom has long held that T cells — specialized immune cells that fight invaders — control CMV. And years of clinical studies supported that view, Hill said. In the 1990s, for example, Fred Hutch’s Dr. Stanley Riddell showed how T cells that were able to home in on a specific strain of CMV could prevent its deadly return.

Previously, randomized trials at Fred Hutch and elsewhere administered high doses of antibodies to patients after transplant to keep CMV from reactivating. The results were all disappointing.

There were occasional hints that antibodies played some role against CMV, but it was a supporting one at best. Researchers in the field deemed them bit players and moved on.

Hill wondered if those observations told the whole story. To find out, Hill, who at the time worked at the QIMR Berghofer Medical Research Institute in Brisbane, Australia, together with a team led by Dr. Mariapia Degli-Esposti at the Lions Institute in Perth, created a new mouse model of CMV reactivation.

They spent five years conducting a series of carefully designed experiments. Here’s the condensed version:

Dr. Geoff Hill speaks with Dr. Albert Yeh
Dr. Geoff Hill, the José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research, speaks with colleague Dr. Albert Yeh in the Hill Lab at Fred Hutch. Photo by Robert Hood / Fred Hutch News Service

They began by infecting mice with murine CMV, the version of the virus that infects mice and other rodents. Just like in most humans, their immune systems wrestled it into dormancy.

Three months later they gave these mice a bone marrow transplant, effectively wiping away their immune systems and replacing them with new immune systems from donor marrow. Some received marrow chock-full of donor T cells. Others received “T cell–depleted” marrow.

The group that received a transplant with T cells got graft-vs.-host disease, or GVHD — a known transplant danger where the donor’s T cells (the graft) start attacking the recipient (the host). CMV reactivated in the GVHD group within three weeks after transplant.

Which was a bit odd: Why didn’t the T cells keep CMV tamped down?

Meanwhile, the group that received the T cell–depleted graft didn’t get GVHD. Their CMV also didn’t reactivate.

Which was even odder: If the mice didn’t have T cells, what kept CMV at bay?

The team wondered if some residual T cells had somehow managed to persist in the mice despite transplant. In their next experiment, they took an extra step after the T cell–depleted transplant that removed every type of T cell as well as NK (natural killer) cells, a group of immune cells also thought to control CMV.

But the virus remained silent.

“So straight away this didn’t seem like the paradigm all of us thought was correct,” Hill said. “Something else is controlling it.”

So Hill and company redid the transplants. This time, the mice getting the transplants didn’t have any B cells, which are the antibody factories of the immune system. They all received a T cell–depleted graft. So now the mice had neither T cells nor B cells and their antibodies.

CMV sprang back to life within 10 days of transplant.

The conclusion was clear: An antibody was controlling the virus.

Hill is quick to point out the study doesn’t boot T cells from the story. They do play a role in protecting a host against CMV reactivation. But they need to share credit with their colleagues.

The research team was initially surprised by the extent to which antibodies affected CMV reactivation, Hill said. “But eventually there was nowhere else to go. The data are the data.” 

Precision medicine

Dr. Michael Boeckh, who heads the Infectious Disease Sciences Program at Fred Hutch, asked Hill the obvious questions after he shared preliminary data:

What did you do differently to challenge dogma? Why did you see the importance of antibodies when everyone else missed them?

The key was specificity.

Many different strains of CMV exist. Hill and Degli-Esposti started to suspect that an antibody had to match a particular strain to have an effect. They looked back at the earlier clinical studies that explored whether high doses of antibodies could protect against CMV reactivation. They had all pooled antibodies from many different patients. The virus-specific fighting power was lost as a result, he reasoned.

Several additional experiments in the new mouse model confirmed that strain-specific antibodies were in fact the key. Even better, they demonstrated that transferring strain-specific antibodies to the transplant recipient can prevent virus reactivation.

That suggests a future therapy. If your body has kept CMV in check for years, doctors could capture those helpful antibodies before your bone marrow transplant, purify and multiply them in the lab, then return them to you afterward. That approach would improve upon today’s current antiviral therapies, which are pricey, often toxic, and can promote drug-resistant CMV strains, Hill said.

Hill and Boeckh cautioned that scenario is far from reality. But they’re laying the groundwork for clinical trials to determine if it’s a possibility.

“The results of these elegant experiments are extremely interesting,” Boeckh said. “The next step will be to see if this all holds true in people.”

Dr. Michael Boeckh in his lab
Dr. Michael Boeckh Photo by Robert Hood / Fred Hutch News Service

An old Fred Hutch foe

The first infectious disease specialist hired at Fred Hutch was Dr. Joel Meyers. He arrived from the Centers for Disease Control and Prevention shortly after Hutch scientists pioneered bone marrow transplantation in the 1970s. His mission: to study and stop the infections that plague transplant patients.

CMV sat atop his to-do list.

The virus was the top infectious killer of bone marrow transplant patients, said Boeckh, who came to Fred Hutch in 1990 to study with Meyers. Through pivotal research, Meyers showed that CMV was responsible for roughly 40 percent of fatalities in the early days of bone marrow transplantation. He went on to identify drugs that started to save lives.

Sadly, Meyers died when he was just 46. But countless Fred Hutch colleagues continued to advance his work against CMV. Experts in basic biology explored the virus at the molecular level. Clinical trials led to new and improved blood tests. Sometimes work on CMV opened new doors; Riddell’s work in the '90s paved the way for studies using T cells to treat cancer.

The work continues. Hutch scientist Dr. Adam Geballe studies the genetic tools CMV uses to pick a host cell’s defenses. Boeckh recently helped conduct pivotal studies that led to the approval of a promising new antiviral drug to prevent CMV infection. And Hill will continue to use his mouse model to ask questions: Should antibodies and T cells share the top billing? Or does one pull a bit more weight?

All that work has helped make CMV a less fearsome foe than it was in the early days of bone marrow transplants. But while mortality rates are down, they’re by no means trivial. To this day a patient infected with CMV faces a poorer outcome after transplant.

Boeckh said Hill’s study is another link in a long chain of work here that spans from laboratories to clinical trials.

“We have a long history of pushing the field forward to try and diminish the impact of this virus,” he said. “This is an exciting addition as we continue to ask and answer questions about CMV.”

Jake Siegel is a former staff writer at Fred Hutchinson Cancer Center. Previously, he covered health topics at UW Medicine and technology at Microsoft. He has an M.A. from the Missouri School of Journalism.

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