Who would have thought that something good might come from a herpes virus?
It plagues one in six American teens and adults, causes genital ulcers and frequently recurs through reactivation of dormant viruses. But researchers have just uncovered a secret about this virus that might eventually bring good news: not for herpes sufferers, but for cancer patients.
At Fred Hutchinson Cancer Research Center, the husband-and-wife team of Drs. Tao Peng and Jia Zhu for years has been carefully picking apart the molecular mechanics of herpes simplex virus type 2, or HSV-2, the cause of genital herpes. Their goal is a better understanding of its maddening cycles of dormancy and reactivation.
Three years ago, their attention was drawn to a small protein known as interleukin-17c, which they found is churned out by skin cells under assault by HSV-2. Perhaps, they thought, the skin cells were using IL-17c to fight off these infections. If so, they might have stumbled upon a new way to block herpes, including HSV-1, which causes cold sores.
In test after test, however, this seldom-studied protein showed no antiviral effect whatsoever.
But the scientists were too curious to give up on IL-17c. They wondered: Why were these skin cells making so much of the stuff, and what was it doing?
What they eventually found astonished them: IL-17c was stimulating the growth of nearby sensory nerve fibers, and the herpes virus itself was goading skin cells to produce it.
'A very smart virus'
Human herpes simplex viruses infect and destroy skin cells, but then they retreat far from the infection site and lie dormant inside bunches of nerve-cell bodies called ganglia. When reactivated, they use the long fibers of nerves to move about. IL-17c appears to operate as a chemical signal that protects and promotes the growth and branching of peripheral nerves. The herpes virus, in a sense, wants to keep those fibers healthy, because they are the roads these viral particles travel in search of new skin cells to infect.
Think of IL-17c as the chief of a road crew, directing construction and upkeep of the highways herpes viruses take on their way to mayhem.
These viruses are ancient, believed to have co-evolved with human beings over millions of years. Somewhere on that evolutionary path, herpes simplex may have learned to orchestrate nerve repair. “It is a very smart virus,” said Peng, who has been studying herpes off and on since he emigrated as a student from Nanchang, China 27 years ago.
In a paper published today in the Journal of Experimental Medicine, the couple and their mentor, Dr. Larry Corey —president and director emeritus of Fred Hutch — report on their discovery that IL-17c appears to be a neurotrophin, a nerve growth factor. Although the human body can produce up to 1 million different kinds of proteins, only a handful have been shown to promote nerve growth. Now, there is a new one on the list.
That serendipitous discovery has opened the door to exciting possibilities.
“Hopefully, we’ve found a substance that naturally repairs neurons — that does it silently, every day, in every human being on Earth,” said Corey, who heads the laboratory in the Hutch’s Vaccine and Infectious Disease Division where Peng and Zhu did their IL-17c research. “If that is truly what its main function is, and we can harness that function, we’re going to do something good for people.”
What Corey and his team have in mind is that IL-17c might one day bring sorely needed relief to cancer patients from one of the most common side effects of chemotherapy: peripheral neuropathy. Nerves adjacent to skin that are damaged by cancer treatments can leave patients with symptoms that range from stabbing pain to dangerous numbness in hands and feet. Each year, according to the Centers for Disease Control and Prevention, an estimated 650,000 Americans receive chemotherapy, just in outpatient clinics alone. Radiation and surgery also take a toll in damaged sensory nerves.
About two of every three patients who are given the most common chemotherapy drugs experience peripheral neuropathy following treatment. Peripheral nerves can rebound, but after six months, symptoms of numbness, tingling or pain are still experienced by 30 percent of patients. The effects can be permanent, and because of loss of sensation, sufferers can have difficulty walking and have double the risk of falls, which can further erode their quality of life. Treatment options for peripheral neuropathy are limited.
Aeronautical engineer and patient activist Janet Freeman-Daily, of Federal Way, Washington, was diagnosed with lung cancer in May 2011. She soon began treatment with carboplatin and Taxol, a mainstay combination chemotherapy.
“I started having neuropathy on that, and it has never gone away,” she said. “There are days when it feels like the bottoms of my feet are burning. Some toes, some other parts of my feet are numb. I can’t sense the floor.’’
Since her diagnosis, she has suffered three falls, one of which in 2015 broke her shoulder. Now she is recovering from a torn tendon in her foot. The cancer news has been better. Freeman-Daily has shown no evidence of disease for four and a half years, and she credits her survival to a later round of precision-oncology therapies that targeted a specific mutation in her tumors.
“As newer drugs are coming out, it’s allowing patients to live longer. That means there are more of us with late-term effects,” she said.
More work ahead
The Fred Hutch finding is novel, and the next step will be to see if IL-17c can be formulated into some kind of topical cream or injectable to repair nerves damaged by chemotherapy. There is a long and uncertain road from a laboratory discovery to a successful drug. The effects of this protein in reducing chemotherapy-related peripheral neuropathy have yet to be tested in animals, let alone humans. The Hutch researchers are now initiating experiments to see if IL-17c measures up to their expectations.
Corey said nerve growth factor, the first neurotrophin to be identified — earning its discoverers a Nobel Prize in 1986 — had been tried against neuropathy, but it actually caused an increase in pain. Another neurotrophin, called BDNF, triggers sensory nerve growth, but its biological activity is short-lived.
The intrinsic appeal of IL-17c is that it functions naturally in the environment where sensation occurs — at the junction of skin cells and nerve fibers. And its connection with herpes simplex is intriguing: In contrast to other related viruses such as varicella-zoster, which causes chickenpox and shingles, HSV leaves no evidence of nerve loss.
“Herpes simplex is a recurrent infection,” said Zhu. “Once a person has it, the virus never leaves them. Periodic recurrences happen all the time, but the patient never really loses sensation.”
Corey pointed out that varicella-zoster does not appear to cause skin cells to produce IL-17c, and reactivations of that virus cause painful nerve damage. HSV-1 and HSV-2, on the other hand, do induce production of the protein, and reactivation of these viruses yields no loss of sensation or neuropathy. This is particularly noteworthy because the herpes viruses reactivate 50 to 100 times more often than varicella-zoster. It is more evidence and grounds for optimism that IL-17c and its receptors on nerve fibers are important in protecting peripheral nerves.
A serendipitous discovery
Peng was a graduate student at the University of Maryland Medical School in Baltimore when he met his future wife, who was a postdoctoral researcher there. Zhu had come to Baltimore from Shanghai, where she had earned her Ph.D. Both were studying herpes, and a romance bloomed. The couple have a son, 17, and a daughter, 15. Zhu furthered her herpes research with Dr. David Knipe, a prominent herpes virologist at Harvard Medical School, while Peng became an expert in genomic analysis at the nearby Whitehead Institute of Biomedical Research in Cambridge. In 2003, they moved to Seattle, where they are affiliated with both the University of Washington and Fred Hutch.
“Jia is a terrific investigator,” said Corey. “She’s very meticulous. She’s developed technologies for detection in tissue of both immune cells and HSV that have been at the forefront. She’s both a good virologist and a good immunologist, and for us that is a wonderful thing.”
The couple’s complementary skills were brought to bear on their herpes research. It was during their efforts to probe the microenvironment where the virus infects skin that Peng first noticed that skin cells were producing IL-17c, a protein that previously had been suspected of causing inflammation in the skin disease psoriasis. For eight months, the research team struggled to find some antiviral effect.
“We had a period of frustration,” Corey said. “If it is not an antiviral, what the hell does it do?”
Zhu admits to a fascination with studying herpes.
“In a tiny piece of tissue, there are a lot of secrets just hiding there, waiting for us to discover,” she said. “There are a lot clues.”
As the IL-17c mystery deepened, she remembered an observation she had made years ago about herpes infection in humans, but had not pursued: Nerve fibers in patients with active herpes infections appeared longer and denser. Could there be a link to IL-17c? Their experiments began to show that nerve cells grew in the presence of it. But why?
It was on Christmas Eve in 2015 when Peng went to Corey’s office to discuss a recent discovery: The nerve fibers in samples of herpes-infected skin were studded with receptors for IL-17c. They matched like a lock and key. That observation, in concert with the finding that the virus was linked to nerve growth, made it obvious that IL-17c was binding to the receptors on the tips of nerve fibers and turning on growth like a switch. They had connected the dots.
“I could see his eyes just totally light up,” said Peng.
During 2016, a succession of detailed experiments provided convincing confirmation that IL-17c was indeed promoting the growth of sensory nerves. The protein also appears to protect nerve fibers from damage, tamping down a natural process of cellular suicide that can occur when nerve tissues are under stress.
Now a new round of research is under way to find out if this nerve-growth protein that promotes growth and survival of nerve fibers might be harnessed to protect or repair the nerves of chemotherapy patients.
Although luck has always played a role in scientific discovery, odds are that nothing remarkable ever comes from blind chance alone. As 19th century French biochemistry pioneer Louis Pasteur famously said: “Fortune favors the prepared mind.”
It was years of dedicated work and focus by Zhu and Peng that ultimately pried this secret from an unwelcome virus. Their efforts have brought them one of the joys of science, the unexpected discovery. With a little more luck, and a lot more work, “something good for people” may indeed come from it.
The National Institutes of Health and the James B. Pendleton Charitable Trust supported this study.
Sabin Russell is a staff writer at Fred Hutchinson Cancer Research Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT, and a freelance writer for the New York Times and Health Affairs. Reach him at srussell@fredhutch.org.
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