Probing the genetics behind herpes viruses' silent threat
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Veterinary Scientist Clinton Jones wants to understand the genetic circuitry that allows a herpes virus to wait silently in animal or human cells, then reactivate and repeatedly attack its host and spread infection. His University of Nebraska research into genes controlling this latency is on the leading edge of breakthrough theories about how herpes viruses cause disease and perpetuate themselves in humans and cattle. These theories offer hope for new herpes vaccines and treatments. Jones works with two viruses, Bovine Herpes Virus-1 (BHV-1) and the closely-related human herpes simplex virus type 1 (HSV-1). Both cause infection by traveling to neurons, specialized cells that transmit messages to the brain. Viruses replicate by commandeering the genetic machinery of host cells, usually killing cells and causing disease symptoms. When BHV-1 or HSV-1 infects a neuron, the virus often shuts off, entering latency and allowing the neuron to survive. Latency may be the key to new herpes virus treatments and vaccines. Latency helps the virus survive by keeping infected host cells alive, allowing the virus to periodically reactivate and infect other hosts, Jones said. How and why herpes viruses become latent is the focus of Jones' Institute of Agriculture and Natural Resources research. "If you could prevent a virus from becoming latent, you could make better vaccines and slow down or inhibit virus transmission," he said. Cattle 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 abortion and disease in calves and don't prevent latency, so vaccinated cattle may spread disease to calves. HSV-1 can infect people's nervous systems, respiratory tracts and gastrointestinal tracts, is a serious venereal disease and is the leading cause of infectious corneal blindness. "Corneal blindness is caused by the virus reactivating from latency and reinfecting the eye over and over," Jones said. "If we could block latency, we could literally stop this disease." 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. Independent research revealed a similar gene in the human herpes virus, but it's not known whether this gene encodes a protein. 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. Neurons are different, Jones said. "Very early in mammalian development neurons stop growing. It doesn't make sense for neurons to undergo PCD because they can't be replaced," Jones said. Jones and others showed that infecting cultured cells or calves with BHV-1 can induce PCD. Jones' recent research revealed the BHV-1 latency-related protein he discovered earlier may promote latency by stopping programmed cell death in neurons. "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 it's on, the virus produces the protein, PCD is inhibited, and 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 USDA competitive grants, a competitive grant from the Elsa U. Pardee Foundation and NU's Center for Biotechnology help fund this research. – Monica Norby |
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Arrows point to red areas of a neuron that are infected with Bovine Herpes Virus-1. When BHV-1 and a closely related human herpes virus infect neurons, the virus often shuts off or becomes latent. There it waits silently to reactivate, attack its host and spread infection. IANR veterinary scientists are studying latency in hopes of figuring out how to prevent it in herpes viruses.
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