Genital herpes comes and goes--at least that's what it looks like to patients. But a mathematical model published in the 18 November issue of Science Translational Medicine suggests that herpes never slumbers. Instead, nerve cells continuously pump out the virus in minuscule quantities over a sufferer's lifetime. If the findings hold, it may be much harder to stop patients from passing on the infection than researchers thought.
As many as one in five people is permanently infected with herpes simplex virus 2 (HSV-2), the most common cause of genital skin ulcers. The virus is transmitted during sex; after infection, it retreats into nerve cells that have their endings in the genital skin. HSV-2 causes no problems in up to 80% of those infected, but a minority suffers from blisters and sores once or twice a month. For decades, most scientists believed that the virus was simply "off" in the intervals between outbreaks, says William Halford, who studies herpes at Southern Illinois University School of Medicine in Springfield.
But that view has come under fire the past decade or so, as researchers showed that the virus is sometimes present in the genital skin even when no lesions are apparent. The new work, by infectious diseases researcher Lawrence Corey and his colleagues at the University of Washington and the Fred Hutchison Cancer Research Center, both in Seattle, goes even further.
Joshua Schiffer, a clinician and mathematical modeler in Corey's group, constructed mathematical models from a large amount of virological and patient data--including the amount of virus present in the skin of patients who took four swabs daily for 60 days. This is what appears to be going on: Nerve cells shed tiny amounts of virus almost constantly inside the genital skin. Frequently, a virus will infect an epithelial cell, which compared with a nerve cells are "real virus factories," says Schiffer: They produce massive amounts of virus that can infect other nearby epithelial cells and can presumably also infect sexual partners. In most cases, infected epithelial cells are quickly killed by CD8+ cells, a type of white blood cells; only occasionally does the infection overwhelm the immune system, resulting in a lesion.
"It's impressive that they were able to build a model that makes sense of a large amount of clinical data," says Philip Krause, a herpes researcher at the U.S. Food and Drug Administration. "It's a very thoughtful way of looking at the data." Halford says the paper should help dispel the notion, still supported by many herpes scientists, that the virus "does nothing" between clinical episodes.
The findings may also explain some properties of antiherpes drugs like acyclovir, says Schiffer. For instance, in a trial where herpes patients took acyclovir to prevent their partners from becoming infected, the drug was only 50% effective. If virus shedding never stops, these drugs have a much harder job, says Schiffer, especially compounds like acyclovir that quickly disappear from a patient's body. To really prevent transmission, drugs would have to last longer or stop the shedding by the nerve cells, he adds--but that's a tall order.