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‘Bottleneck’ may limit herpes outbreak

PRINCETON (US) — Just one or two individual herpes virus particles attack a skin cell in the first stage of an outbreak, resulting in a bottleneck that may make the infection vulnerable to medical treatment.

Unlike most viruses that spread to new cells by bombarding them with millions of particles, herpes simplex virus type 1 (HSV-1)—a virus that causes cold sores and genital lesions—requires just one or two viral particles to infect a skin cell in the first stage of cold sore formation, a study in Proceedings of the National Academy of Sciences reports.

“The fact that just one or two virus particles are involved is surprising because these viruses can replicate themselves hundreds of times in a single cell,” says Matthew Taylor, first author of the study and a postdoctoral researcher in the laboratory of Lynn Enquist, professor of molecular biology at Princeton University.

The bottleneck occurs when HSV-1 particles, which can lie dormant in the cells of the nervous system for decades after initial infection, awaken and invade a nearby skin cell, the first stage in sore formation. Once inside the skin cell, a single viral particle multiplies and spreads millions of copies to nearby skin cells, creating a visible lesion or “cold sore.” The virus can then spread to new individuals through skin-to-skin contact.

This restriction to one or two particles limits the genetic diversity of the virus that spreads to the next individual, Enquist says. This puts the virus at a disadvantage, because having a variety of distinct genomes enhances the overall chances of the virus surviving and spreading. A well-known example of a virus that relies on genetic diversity to thrive is HIV, which involves large numbers of viral particles with distinct genomes.

In the case of herpes viruses, Enquist says: “The number of different genomes that infect the cell is remarkably low, so any mutations that weaken the virus are unlikely to survive. Only the most fit viral particles will survive and replicate in the epithelial [skin] cells, and be available to transmit to the next individual.”

Although bottlenecks can ensure that only the most fit viruses are transmitted to the next individual, they also can be points at which the infection is more susceptible to immune system responses and drug treatments.

The findings suggest that other viruses related to HSV-1—known as alpha-herpes viruses—may have similar bottlenecks,  including herpes simplex viruses type 2, which causes cold sores and genital lesions, and varicella zoster virus, which causes chicken pox and shingles. It remains to be determined if a bottleneck exists for other viruses that spread from infected neurons, such as poliovirus and the West Nile virus.

“This work changes the way that we think about herpes virus spread,” says Julie Pfeiffer, an associate professor of microbiology at the University of Texas Southwestern Medical Center who is familiar with the study but had no role in it. “This study demonstrated that these neuron-to-epithelial cell viral-transmission events are surprisingly efficient, but they are initiated by a very small number of viruses. This work has interesting implications for herpesvirus transmission and evolution.”

Color-coded genomes

To determine the number of virus particles that infect the skin cell, the researchers constructed three genetically unique viral genomes labeled with either red, green, or blue fluorescent tags, and then infected cells with the particles and analyzed them for the presence of the three colors. They counted the number of cells containing one, two, or all three colors and used statistical analysis to determine the number of unique viral genomes expressed in each cell.

The method, which was originally developed by Kobiler, Enquist, and colleagues in Princeton’s mathematics department and initially published in 2010 in Nature Communications, revealed that most skin cells express less than two viral genomes on average.

Taylor then filmed individual virus particles of pseudorabies virus, a model alpha-herpes virus that infects animals, as the particles exited neurons and entered skin cells and found the bottleneck limiting infection to one or two particles exists for pseudorabies virus as well.”It is really amazing to see this happening in living cells.”

Oren Kobiler, a former Princeton postdoctoral researcher now at Tel Aviv University, is a co-author on the study, which was supported by the National Institutes of Health and the American Cancer Society.

Source: Princeton University

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