The Science of the Virulent Herpes Simplex
Researchers probe the protein that drives worst-case viral behavior in the herpes simplex virus.
Published December 30, 2003
By Margaret W. Crane
Academy Contributor

The Herpes simplex Virus (HSV) is nothing if not cunning. It generally starts out on the mouth or genitals, moves between the skin’s surface and the sensory neurons, where it makes itself at home, and periodically resurfaces to create lesions near the original site. From the Greek herpein, meaning “to creep,” the herpes simplex bug uses the human cell as a factory for self-replication and then thwarts the body’s ability to fight back.
HSV comes in two forms: HSV-1 is usually content to make mischief by creating cold sores, and HSV-2 is the main cause of genital herpes. These fraternal twins belong to an extended family of eight human herpes viruses, including those associated with mononucleosis, chicken pox, shingles, and Kaposi’s sarcoma, among other diseases.
People typically do not die from the herpes simplex virus, but it is a cause of widespread physical and psychological suffering, said Ken S. Rosenthal, PhD, professor of microbiology and immunology at Northeastern Ohio Universities College of Medicine, during his talk at the Academy this October. Oral herpes affects from 50% to 80% of the adult population in the United States, while genital herpes afflicts more than 20%. In some developing countries, the latter number can soar to upwards of 70%.
“The herpes simplex virus is a significant human pathogen by dint of its disease-producing capability,” said Rosenthal. “It also gives us a tool for studying the body processes it takes over. To make matters more complex, all herpes simplex viruses are not created equal. We’ve found that tiny variations in a particular strain’s genetic structure translate into vast differences in its ability to spread and wreak havoc in the body.”
A Thorny Paradox
Most strains of HSV are mild, but for people at risk—a group that includes newborns and the immunocompromised—even a mild viral infection can spiral out of control and overwhelm the body’s resistance. Some strains have the ability to spread between and along the neurons, travel to the brain, and cause encephalitis, a rare but deadly inflammatory brain disease that can strike the healthy and vulnerable alike.
Rosenthal and his collaborators have shown that the unique molecular structure of one protein, known as ICP34.5, is different in these virulent strains and can promote their encephalitic disease potential. During their investigation, however, the researchers bumped up against a thorny paradox.
“In the lab, we always prefer to study a virus that’s very ‘out there,’ visible, and easy to work with,” said Rosenthal, “but in the body, a visible virus is one that is quickly eliminated by the immune system. Herpes simplex is especially good at hiding out in cells and eluding the immune response. That’s why a strain of HSV that looks ‘strong’ in the lab may not actually be the most virulent in real life.”
It was HSV that was the suspected cause when an infant died shortly after birth at a local Ohio hospital in 1991. John Bower, an infectious disease physician on Rosenthal’s research team, performed the autopsy and collected cells from the infant’s brain, lung, and gastrointestinal tract. “John’s efforts were the beginning of our quest to understand what happened,” said Rosenthal.
The Neuroinvasive Culprit

The researchers isolated a virulent strain of herpes simplex (SP7) from the baby’s brain cells, cultured it, and mapped its genetic structure. Then, one of Rosenthal’s graduate students, Dr. Hanwen Mao, currently a postdoctoral fellow at the National Institute of Allergy and Infectious Diseases of the NIH, engineered an attenuated virus, but replaced its form of the ICP34.5 protein with the ICP34.5 protein that is unique to SP7. Sure enough, when Mao injected the new ICP34.5-hybrid virus into laboratory mouse models, the mice developed symptoms of partial or total paralysis.
“It was clear that the SP7 form of ICP34.5 was the neuroinvasive culprit,” said Rosenthal, “but there are still a whole host of questions surrounding how this protein’s unique structure determines such specific viral behavior.”
The world of cell biology is all about location, he continued. A protein’s structure is what permits it to travel to different places in the cell, and different forms of ICP34.5 preferentially seek out different cellular locations.
Meanwhile, the invaded cell doesn’t like the stepped-up synthesis of protein that is required to make new viruses. In an attempt to restore order, it activates phosphorylation, an enzyme-driven process that adds phosphate groups to the gatekeeper protein to slow or stop protein synthesis. ICP34.5 counters the cell’s self-regulating efforts by turning on protein phosphatase 1 (PP1), a key cellular enzyme, to remove the phosphate block. As a result, viral proteins are made, new viruses are produced, and the cell faces certain death.
Unique Biochemical Actions
The SP7 form of ICP34.5 also helps HSV escape from the body’s defenses and find a path through the neuronal highway. Normally, the body uses interferon to activate phosphorylation and protect itself from viruses, and it uses antibody to promote their elimination. The SP7 form of ICP34.5 offers two mechanisms that HSV can use to get around these obstacles. In addition to its action on PP1, the SP7 form of ICP34.5 directs the virus to cell-cell junctions, a strategy that promotes its passage up the neuronal pathway to the brain and hides it from antibody.
ICP34.5, and the SP7 strain of HSV in which it is embedded, turned out to be the biochemical component behind the newborn’s death from disseminated herpes infection. Rosenthal’s hypothesis—that the SP7 form of ICP34.5 provided unique biochemical actions that drove this virus to the brain of the newborn and caused its death—was thus supported by the laboratory findings.
Beyond its well-known embarrassing and painful symptoms, HSV has an even more serious side that lends particular urgency to herpes research. The virus can pass from mother to newborn, with deadly consequences. In the developing world, genital herpes has been identified by the World Health Organization as a major facilitator of HIV transmission. Although antiviral treatments are available, there is no way to eliminate a herpes infection.
Some scientists are investigating novel drug candidates, and others are testing vaccines to help control the virus. Finally, however, their work depends on the results of basic research. By clarifying how HSV spreads in the body, Rosenthal et al. are advancing the research of those who seek to control the virus’s spread in the community.