Hope for New Herpes Vaccines, Treatments

CONTACTS:
Clinton Jones, Ph.D., professor, veterinary and biomedical sciences, (402)472-1890

Vicki Miller, IANR science writer, (402)472-3030

NU Researchers Target Latency to Control Herpes Viruses

LINCOLN, Neb. -- University of Nebraska-Lincoln veterinary science research is helping to unravel the mystery of how herpes viruses cause disease and perpetuate themselves in humans. This research offers hope for new herpes vaccines and treatments for the 70 percent to 90 percent of adults affected by herpes simplex viruses.

Research findings are reported in Friday's (Feb. 25) issue of Science magazine. In that article, Clinton Jones, NU Institute of Agriculture and Natural Resources virologist, Steven Wechsler, virologist at the Ophthalmology Research Laboratories at Cedars-Sinai hospital in Los Angeles, and colleagues discuss the mechanism that controls latency. Latency is the process that allows a herpes virus to wait silently in cells of organisms it infects, then reactivate and repeatedly attack the host and spread infection. Jones' work shows that a gene called the latency-associated transcript (LAT) keeps the host cell alive by inhibiting programmed cell death, the host's natural reaction to infection.

Jones and colleagues work with two viruses, human herpes simplex virus type 1 (HSV-1) and closely related Bovine Herpes Virus-1 (BHV-1), which infects cattle. Both cause infection by entering the host through the eye, nose or mouth and traveling to neurons, specialized cells that transmit messages to the brain.

Their most recent work focuses on HSV-1, which can infect the human nervous system, respiratory tract and gastrointestinal tract, is a serious venereal disease and the leading cause of
corneal blindness resulting from infection.

Viruses replicate by commandeering the genetic machinery of host cells, usually killing cells and causing disease symptoms. But when HSV-1 infects a neuron, the virus often shuts off, entering a latent state and allowing the neuron to survive.

This latency, when the virus silently waits to reactivate and spread, may be the key to new herpes virus treatments and vaccines. Latency helps the virus survive by keeping infected host cells alive and allows the virus to periodically reactivate and infect other hosts, Jones said.

How and why herpes viruses become latent is the focus of Jones' research.

"If you could prevent a virus from becoming latent, you could make better vaccines and slow down or inhibit virus transmission," Jones said. "Corneal blindness is caused by the virus reactivating from latency and re-infecting the eye, over and over. If we could block latency, we could literally stop this disease."

Cattle infected with BHV-1 may suffer bovine respiratory complex, eye disease, miscarriage and, occasionally, lethal encephalitis, problems that cost cattle producers more than $500 million annually. Available vaccines can cause disease in calves and abortion, and don't prevent latency so vaccinated cattle may spread disease to small calves.

In his early BHV-1 work, Jones discovered that the latency-related gene encodes a latency-related protein. The protein is found in neurons during latency. He thought this protein might help regulate latency.

In 1996, at the same time Jones was exploring the "how" of latency, a relatively new concept called programmed cell death (PCD) emerged from cell biology research and offered clues to "why" this was important for latency.

PCD is a natural function for many cells, which must die and be replaced as organisms grow. But neurons are different, Jones said.

"Neurons stop growing very early in mammalian development. It doesn't make sense for neurons to undergo PCD, because they can't be replaced," Jones said.

Jones' recent research reveals that the LAT gene can block PCD. When rabbit neurons are infected with viruses lacking the LAT gene, extensive PCD occurs. In neurons infected with viruses expressing the LAT gene, PCD is blocked and most neurons survive.

"We are the first to demonstrate that latency gene products inhibit cell death," Jones said. "We believe this prevents the virus from destroying its site for latency and so helps perpetuate the viruses in their natural hosts."

The latency-related gene acts like a switch. When its on, the virus produces the protein, PCD is inhibited and both the host cell and virus survive. Finding a way to switch the gene off could be a way to treat and inhibit the spread of viral diseases.

"We know that the latency-related genes inhibit PCD, but we don't know how. We are studying that now," Jones said. Two U.S. Department of Agriculture competitive grants, a competitive grant from the Elsa U. Pardee Foundation and NU's Center for Biotechnology help fund this IANR Agricultural Research Division research.

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