• The Next Frontier In Herpes Simplex Research

    by Mary Silva

    For two decades, Nancy Sawtell, PhD, has probed the mysteries of the herpes simplex virus (HSV), and the effects of its long-term residence in our bodies. Now, she is taking her research to the next frontier, exploring the effects of deep space radiation on the reactivation of HSV. Sawtell will begin a NASA-funded study this year, together with fellow Cincinnati Children’s researcher Michael Williams, PhD, and Richard Thompson, PhD, of the University of Cincinnati.

    Estimates are that as much as 90 percent of the world population is infected with HSV. Once acquired, there is no getting rid of it – there is no treatment, and no cure. After initial infection through oral or mucosal tissue, the virus makes its home in our neurons, where it lives in a mostly latent state for our lifetime.

    NOT YOUR AVERAGE ASSAULT

    Astronauts are as likely as the rest of us to be carrying latent HSV infections in their central nervous systems. If a mere fever can trigger a reactivation of the virus here on earth, what effect might travel into space have?

    “Astronauts, like most humans, have latent virus in the brain. And they are concerned about deep space radiation exposure to heavy ions and other molecules over prolonged time in space,” says Sawtell, a researcher in the Division of Infectious Diseases. “They know that after a year, every cell in the body will be hit by a heavy ion. They want to understand the effects of radiation in a brain that has the latent virus.”

    WHAT CAUSES REACTIVATION

    Sawtell and Thompson made a breakthrough discovery several years ago when they identified the culprit responsible for HSV’s exit from latency – the viral protein VP 16. Their discovery, published in PLoS Pathogens in 2009, paved the way for better understanding the workings of HSV.

    Since then, Sawtell has examined the toll that the lifelong cycle of latency and reactivation takes on our central nervous system. She already has evidence from animal studies that the inflammation caused by the virus’s reactivation causes lesions in the brain, particularly in genetically predisposed individuals.

    WORSENING WITH AGE

    Working from an idea proposed by British researcher Ruth Itzhaki, PhD, that HSV’s chronic latency-infection cycle might cause Alzheimer’s disease in certain individuals, Sawtell pursued her own studies in which animals with the genetic variant APOE4 were infected with HSV. She found that more of the virus got into the brains of the animals with the APOE 4 allele.  After reactivating the infection periodically, she watched lesions form in the brains of the animals as they aged.

    It was the first evidence Sawtell had seen that reactivating the virus actually caused lesions in the brain. “We saw quite remarkable lesions related to repeated reactivation,” she says.

    MICE IN SPACE

    Now, she will continue her work into HSV’s effects on the central nervous system by exposing mice to simulated deep space radiation. Beginning in January, she will ship mice to the particle accelerator at the Brookhaven National Laboratory in New York.

    “The animals will be exposed to heavy ions and protons, then we’ll bring them back here and do long-term studies looking at the combination of repeated stresses to reactivate the virus and behavioral outcomes. We’ll also be imaging the brain and in the end will look at lesions,” Sawtell says.

    The mice in the simulation study will be compared to controls of animals exposed to the normal stressors experienced by most humans, to see whether and how deep space exposure accelerates the risk of neurological problems from HSV infection.

    Sawtell believes that studying the effects of these simulated deep space assaults will provide new insights into a virus that continues to fascinate scientists and escape our grasp. And she wonders if our inability to fully eradicate it might not be such a bad thing.

    “We talk about eliminating the virus, but what we don’t know is, what would that do to the viral biome?” she asks. “These viruses probably provide positive as well as negative effects. Some researchers report that if we didn’t have viral infections we might have more cancer. There are tradeoffs potentially that we don’t understand.”


    THE “SENSITIVE” VIRUS

    The sensitive virus.

    The herpes simplex virus (HSV) not only has a feel for when the cell it inhabits is stressed, but also has the ability to restrain its reactivation, says Dr. Nancy Sawtell.

    “It is a very aggressive virus. When allowed to replicate freely, it will kill a cell within 18 hours. But it has built-in regulatory mechanisms to make itself able to survive in the delicate environs of the nervous system.”

    So reactivation often might affect only one or two neurons.

    “Single neurons can reactivate with no symptoms at all,” says Sawtell. “People who get no obvious symptoms are most likely periodically reactivating in their peripheral and central nervous system.”

    But even though we may be unaware of them, these episodic flareups take their toll, causing us to unintentionally transmit the virus to others while wreaking slow havoc on our own systems.

    “Because this happens over and over again,” Sawtell says. “Not to the same cell, but to different cells. And depending on the immunological genotype-phenotype of the host, it can cause no problems or it can cause serious problems. Because the host responds in an overly abundant way to that insult. So the inflammatory response accrues over time and you get these lesions.”

  • Dr. Nancy Sawtell’s latest work with HSV will study the risks of space exploration on virus reactivation.

    Dr. Nancy Sawtell

  • Mice in space