Hutch News

Herpes' vigilant foe: Volunteers in Seattle

Sept. 19, 2002
Christine Posavad and aide using microscope

As Dr. Christine Posavad (left) looks on, Clinical Research Division laboratory aide Angela Chintella examines herpes-specific T cells.

Photo by Todd McNaught

To many people, herpes infection signifies little more than a social stigma.

But Dr. Christine Posavad knows better.

Her vaccine research in the Clinical Research Division recognizes that the implications of herpes are much worse, even fatal, because one form of the virus can boost the risk of acquiring HIV, which causes AIDS.

Herpes simplex virus (HSV) type 2 is best known as the cause of genital herpes, a sexually-transmitted disease that results in painful sores.

Yet its role in transmission of AIDS has given the virus the reputation of a major public-health problem.

Posavad, an associate at Fred Hutchinson and a research assistant professor at the University of Washington, is working to develop a vaccine or other prevention strategy for (HSV) type 2 which might ultimately help to minimize the spread of HIV.

Vaccines and therapies that prevent HSV-2 transmission have thus far been ineffective.

Mysterious resistance

But Posavad and her colleagues suspect that improved approaches could develop from their studies of an unusual group of individuals who mysteriously resist HSV-2 infection, despite frequent exposure to the virus via their infected sexual partners.

Thanks to this dedicated population of research volunteers, Seattle might be the first city from which a successful herpes-prevention strategy emerges.

Posavad works with Dr. Larry Corey, director of the infectious diseases program, as well as virologists at the center, the University of Washington and Northwestern University.

Posavad and Corey search the immune systems of the volunteers for clues to their resistance that might be exploited to help engineer resistance in the general population through vaccines or other manipulation of the immune-system.

HSV enters the body by way of linings of the mouth or genital tract known as mucosa. Upon initial infection, many develop painful sores and sometimes, flu-like symptoms such as headaches and muscle pain.

Those who experience few or no symptoms may never realize they are infected and can unwittingly transmit the infection to others.

"Upon initial infection in epithelial cells, the virus replicates to produce more virus," Posavad said.

"Later, the virus infiltrates nervous-system tissue, where it remains in a non-replicating latent state with little gene expression."

Reactivation of HSV, triggered by known and unknown factors, can continue to cause symptom flare-ups for life.

HSV-2 eludes surveillance and control by the human immune system, which system mounts two defense strategies to recognize and destroy pathogens: proteins called antibodies and specialized cells known as T-cells.

Scientists have had poor luck identifying the parts of the virus that trigger an immune response and that could be exploited for vaccine development, Posavad said.

"We still don't know what factors are important for resistance to HSV infection," she said.

"We do know that as far as mounting an immune response against the virus, T cells are more important than antibodies. The reason existing vaccines have been unsuccessful is likely because they have not elicited a successful T-cell response."

Because the T-cell response seems to be most important in controlling HSV-2 infection, Posavad suspects that those who resist infection may have unique or especially potent T-cell responses.

With a recently funded grant from the National Institutes of Health, Posavad will examine the immune responses of a group of volunteers who resist HSV-2 infection despite chronic exposure to the virus.

These individuals participate in studies at the UW Virology Research Clinic, overseen by Dr. Anna Wald, associate professor of medicine.

Some study volunteers do possess T cells that react with HSV-2, suggesting previous exposure to the virus. Such individuals, who do not produce antibodies to HSV, a reaction considered the gold standard for diagnosing HSV infection, are said to have acquired resistance to the virus.

Altered versions of receptors

Others may be genetically predisposed to resist HSV-2 infection by producing altered versions of the cellular receptors the virus uses to attach to and enter mucosal cells. An analogous situation occurs for a subpopulation of people who resist HIV infection.

Either or both mechanisms may yield insight into strategies to essentially mimic resistance in susceptible individuals, either with vaccines or immunotherapy, a treatment in which a person's own immune system is stimulated to provoke a protective response.

None of these studies would be possible, Posavad said, without the help of study volunteers at the UW Virology Research Clinic.

"We have an incredible patient population in Seattle that is interested in helping us understand the disease," she said.

"This makes it easier to answer questions about factors controlling or preventing HSV infection in humans, which is critical because animal models haven't been helpful in some cases. It makes Seattle a unique place to study this disease."

 

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