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Oral Herpes

Genetically Prone to Outbreaks?

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Link between genes and oral herpes susceptibility discovered

While the common cold and overexposure to sunlight are suspected triggers of oral herpes outbreaks, genetic factors may be at play as well. Researchers at the University of Utah School of Medicine recently discovered a region of the human chromosome linked to more frequent outbreaks of oral herpes. Results of their research were published in the February 1 issue of the Journal of Infectious Diseases.

The study began with the objective of identifying human genes linked to herpes simplex labialis, or oral herpes. Researchers performed serological testing on 421 volunteers from 39 families enrolled in the Utah Genetic Reference Project, a genomic study of multigenerational Utah families. Study participants who tested positive for HSV-1 were asked to record details on any outbreaks of oral herpes, including past episodes, promdromal symptoms and triggers. Based upon the information reported, participants were classified as either “frequently affected,” “mildly affected,” or “unaffected,” as determined by the number of annual outbreaks.

Once the participants were categorized, researchers conducted a genetic analysis on only those in the “frequently affected” (2 or more outbreaks a year) and “unaffected” (never reported an outbreak) groups, to make the distinction between the groups as clear as possible. Those that were in the “mildly affected” group, or were uncategorized, were excluded from the analysis. The analysis identified a region on human chromosome number 21 that contains genes that may be linked to increased susceptibility to oral herpes outbreaks.

The discovery of this genetic link could lead to a better understand of HSV infection and the factors that influence the frequency and severity of infection. As study author John D. Kriesel, MD, noted, “One or more of these genes might make excellent targets for new drugs to reduce the number of herpes outbreaks.” Implications for future research aren’t necessarily limited to oral herpes. According to Kriesel, “Finding a drug target to reduce the frequency of cold sores would be even more valuable if we could expand our study results to include genital herpes or herpes keratitis, and that’s something I’d like to do.”


Bringing Herpes Out of Hiding

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Uncovering the key to latency may bring an end to oral herpes, researchers hope

One distinguishing characteristic of the herpevirus family of viruses is latency. Rather than being cleared by the body’s immune system, the herpes simplex virus establishes permanent residence in a nerve root called a ganglion. While the virus is in an active phase, the immune system is capable of responding, sending out antibodies to fight off infection. But when herpes goes into hiding during its latent (or inactive) phase in the ganglia, it remains beyond the immune system’s reach.

But what if we could bring the herpes simplex virus out of hiding? Researchers at Duke University in Durham, NC looked at that question and in the process have uncovered a new key to understanding latency and HSV-1.

In a joint statement, Professor Bryan Cullen and Jennifer Lin Umbach, Ph.D. of the Duke Department of Molecular Genetics and Microbiology and Center for Virology, commented on the impact of their research: “Our work provides, for the first time, a molecular understanding of how HSV-1 establishes a life-long latent infection in the nerve cells of the face, and how it reactivates from latency to cause cold sores . . . The work we have performed provides a basis for the development of anti-HSV-1 drugs that might be able to permanently clear HSV-1 from

The Duke research team studied the one molecular product produced by the herpes simplex virus during its latent phase—latency associated transcript RNA or LAT RNA. They were able to demonstrate, in studies of mice, that LAT RNA is processed into microRNAs—single-strand RNA molecules. These microRNAs block the production of proteins that make the herpes virus turn on active viral replication. As long as there is a sufficient supply of microRNAs, the herpes virus will stay latent, or inactive.
The potential for treatment lies in learning how to tip the balance and regulate the production and supply of microRNA in order to activate the virus. “Inactive virus is completely untouchable by any treatment we have. Unless you activate the virus, you can’t kill it,” Cullen commented.

Cullen and his team are testing a new drug designed to very precisely bind to the microRNAs that keep the virus dormant. If it works, the virus would become activated and start replicating. Once the virus is active, a patient would then be treated with antiviral therapy to effectively kill the virus.“In principle, you could activate and then kill all of the virus in a patient,” Cullen said. “This would completely cure a person, and you would never get another cold sore.”

Interesting as this new discovery is, many years of research lie ahead before researchers can explore the possibility of development a new treatment. As Cullen and Lin commented, “We anticipate approximately 2 years of animal experiments in mice followed by approximately 1 year of toxicity studies in other animals, followed by small studies in healthy volunteers. After that, assuming things go well, this drug might proceed to clinical trials in HSV-1 infected individuals. It is very possible that the drug candidate might fall out at any of these stages, due to lack of effectiveness or some unanticipated side effect.”

While the Duke research team has focused on HSV-1, they hope that their work will translate into a better understanding of latency and HSV-2 as well. As Cullen and Lin indicated, “All our work so far has been on HSV-1 . . . but HSV-2 is quite closely related. We have begun work to see if the lessons we have learned in HSV-1 also apply to HSV-2, and should know this by the end of the year. If these lessons do hold, then we might hope to start animal trials for an anti-HSV-2 drug in early 2009. However, our initial data indicate that HSV-1 and HSV-2 will require distinct drug therapies.”


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