Discovery Of Protein That Reactivates Herpes Simplex Virus Helps Solve Medical Mystery

ScienceDaily (Mar. 26, 2009) — Research in PLoS Pathogens appears to solve a long standing medical mystery by identifying a viral protein, VP16, as the molecular key that prompts herpes simplex virus (HSV) to exit latency and cause recurrent disease.

Led by researchers at Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, the landmark study points to a molecular target for designing improved HSV vaccines and treatments. It also could direct refined engineering of HSV viruses used in cancer therapy, the investigators said.

The study was conducted in collaboration with the Medical Research Council Virology Unit of Glasgow, Scotland.

The two distinct lifestyles of HSV – active and latent – were first proposed 80 years ago. The virus replicates itself at the body surface, producing thousands of copies that can be transmitted to other people. In neurons, however, the virus can enter a silent state, where the viral genetic code can be maintained for the lifetime of the infected person.

"Our current findings show that, in elegant simplicity, the herpes simplex virus regulates this complex lifecycle through the expression of VP16," said Nancy Sawtell, Ph.D., author and researcher in the Division of Infectious Diseases at Cincinnati Children's Hospital Medical Center.

The study points to what causes the virus to periodically reactivate in latently infected neurons, prompting new rounds of virus replication at the body surface. By understanding how HSV achieves this complex interaction inside the human nervous system, researchers can gain crucial insight into how to control the spread of the virus. At present, there is no way to eliminate latent virus or prevent the virus from exiting latency. There also are no effective vaccines to protect people who are uninfected and transmission rates remain high, the researchers said.

In the study, the research team simulated high fever in a mouse model of HSV infection, demonstrating that VP16 must be produced before the virus can exit the latent state in neurons. Fever has long been known to induce HSV reactivation, and recurrent lesions are often called cold sores or fever blisters because of this association. In the vast majority of neurons, the virus remains latent. In a few neurons, however, the scientists observed that fever in the mice led to a stochastic, or random de-repression of VP16, causing the virus to exit latency and reactivate.

"This completely changes our thinking about how this virus reactivates from latency," said Richard Thompson, Ph.D., co-author and researcher in the Department of Molecular Genetics, Biochemistry and Microbiology at UC. "Instead of a simple positive switch that turns the virus on following stress, it appears instead to be a random de-repression of the VP16 gene that results in reactivation."

The leading infectious cause of blindness and acute sporadic encephalitis in the United States, HSV-1 is usually acquired during childhood. Both HSV-1 and HSV-2 can be sexually transmitted diseases that when passed to newborns during birth causes a severe and often fatal infection. As many as 80 percent or more of people are infected with HSV. Most of the time, people carrying the virus do not have symptoms, although they can still transmit the virus.

The researchers hypothesize that HSV usually remains latent because VP16, which normally enters the cell with the virus particle, does not make the long trip the virus takes through the nervous system and isn't transported efficiently to the nerve cell nucleus.

Future studies will use this new information to develop strategies to prevent or control herpetic disease, said Dr. Sawtell, who also is an associate professor of Pediatrics at UC.

Funding support for the study came from National Institutes of Health.

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The above story is reprinted from materials provided by Cincinnati Children's Hospital Medical Center, via EurekAlert!, a service of AAAS.

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Discovery could lead ways to prevent herpes spread

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Recently enveloped herpes simplex virion in the perinuclear space of an infected cell.

(Medical Xpress) -- Herpesviruses are thrifty reproducers -- they only send off their most infectious progeny to invade new cells. Two Cornell virologists recently have discovered how these viruses determine which progeny to release.

The College of Veterinary Medicine researchers report in the Aug. 23 (108:34) issue I of the Proceedings of the National Academy of Sciences on the mechanisms of this quality-control system, which helps streamline viral reproduction to optimize its spreading.

The virologists identified proteins in the nuclear membranes of infected cells that control which viral products exit. This map could be used to identify new targets for future drugs that would hamper viral reproduction by clogging inspection pathways to trap viruses in the cells they first infect.

"When a herpesvirus hijacks a cell, it turns the nucleus into a viral production factory," said Joel Baines, the James Law Professor of Virology, who co-authored the study with postdoctoral research associate Kui Yang. "It makes protein shells called capsids, stuffs them with viral DNA and ships them out of the nuclear membrane to infect new cells. But errors in the assembly line leave some capsids empty, without DNA, and shipping these is a waste of resources."

When capsids bud from the nuclear membrane, they take pieces of it with them, forming protective lipid envelopes that let them move to new cells. Empty capsids can't reproduce, so the virus only allows capsids with DNA through. How the membrane could determine whether the capsid had DNA or not was a mystery until Yang and Baines mapped its method.

"We found clamplike proteins on the surface of herpesvirus capsids that hold them together and keep them from bursting when they're stuffed full of DNA," said Baines. "Those with DNA have far more of these than empty capsids. We also found a protein complex living in the host cell's nuclear membrane that binds to these structural support proteins, selecting DNA-filled capsids to pull through the membrane. Thus the virus releases only its most infectious particles."

Various species of herpesvirus.

This streamlining process has helped herpesvirus species spread prevalently and permanently across all animal species. Eight of the 25 known viruses in the herpes family regularly infect humans, posing a leading cause of human viral infection.

Once in a body, herpesvirus stays for life. It can flare up at any time, causing symptoms and diseases, ranging from infected sores to brain inflammation, birth defects and cancers of the nose, throat and lymphatic system. Though usually not fatal, herpes can prove dangerous to patients with weak immune systems, such as those with HIV/AIDS or infants who contract HIV/AIDS from their mothers.

There is no cure for herpes, but Baines' map illustrates a viral reproduction system that can be subverted.

"Take away either component, the capsid's clamplike proteins or the membrane's inspector proteins, and nothing escapes the host cell," said Baines. "This opens the door to developing drugs that could block the interactions between these protein complexes, covering the binding sites to clog the system so that no viral particles get through. This would significantly slow or even stop the virus's spread between cells. Our lab is now working on even more detailed maps of these proteins' exact interaction sites that will help drug developers pinpoint precise targets to thwart viral reproduction."

The research was supported, in part, by the National Institutes of Health.

Provided by Cornell University (news : web)

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