A beautiful problem to study

Bill Snyder
Published: April, 2004

The battle against HIV actually had its beginnings during the “war on cancer”—years before the first AIDS case was reported.

Three-dimensional image of a reovirus particle, a common pathogen used as a model for studying viral infections. This image, a computer reconstruction of cryo-electron micrographs of several reovirus particles, shows an outer or capsid protein (blue) used to infect cells, and a core protein (yellow) important in replication.
Image prepared by Emma Nason and B. V. Prasad (Baylor College of Medicine) and Denise Wetzel and Terence Dermody (Vanderbilt University School of Medicine).
In the 1960s, scientists were trying to figure out how certain viruses could cause tumors. One result of that research was the discovery of reverse transcriptase, the enzyme that allows RNA viruses to make DNA copies of themselves inside the cells they infect. Viruses that do this are called “retroviruses.”

By the time AIDS came along in the early 1980s, scientists were able to test tissues and blood for the presence of reverse transcriptase. The detection of the enzyme was an important clue that the disease was caused by a retrovirus. It led—in 1984—to the simultaneous discovery of HIV in the laboratories of Drs. Robert Gallo and Luc Montagnier.

Since then, AIDS research has accelerated, thanks in part to technologies such as the polymerase chain reaction, which allows rapid identification of genetic sequences.

Other clues are emerging from the study of relatively harmless viruses in laboratory animals. Among the most valuable are reoviruses, a family of RNA viruses that include rotaviruses. In humans, reovirus infection usually does not result in anything more serious than a mild cold or diarrhea, but infection during the first weeks of life—in rare instances—can cause bile duct scarring and resulting destruction of the liver.

Terence Dermody, M.D., who directs the Elizabeth B. Lamb Center for Pediatric Research at Vanderbilt, is an expert on reoviruses. Through their studies, he and his colleagues have gained an appreciation for the remarkable capacity of viruses to “home” to their target cells in the body, to dock in an intricately specific manner to the cell surface, slip into the cell, replicate and assemble themselves precisely into new packages of infectious material.

Using methods such as X-ray crystallography and cryo-electron microscopy-three-dimensional image reconstruction, by which researchers can visualize frozen viral particles and construct 3-D images of them with the help of a computer, “we can address fundamental structural questions to understand—at an atomic level of resolution—how two proteins interact to create an important biology,’’ such as how the virus docks to its target cell, Dermody says.

This information is yielding insights into other, more virulent microbes, such as herpes simplex virus and West Nile virus, which cause encephalitis.

The researchers also are trying to construct potential vaccines for other viruses such as HIV, by introducing HIV genes into the reovirus genome. Because reoviruses are relatively innocuous, extremely stable and trigger strong immune responses, they could be a safe and effective way to vaccinate against their more dangerous cousins.

Unraveling the biology of reoviruses “is a fascinating problem … a beautiful problem to study,” Dermody says. “It keeps us up at night.”

Cancer-causing viruses also are an important research avenue. For example, vaccines have been developed to prevent infection by the hepatitis B virus, which can cause liver cancer, and infection by the human papilloma virus (HPV), which causes half of all cervical cancer.

Studies of cancer-causing viruses in the 1960s and 1970s laid the groundwork for understanding how cancer can develop. Oncogenic viruses can produce tumors by blocking genes and proteins that control normal cell growth and division. Mutations in these genes also can trigger abnormal cell growth—even in the absence of viral infection.

“Viruses are always better cell biologists than we are,” Dermody explains. “So if we can hitch a ride on a virus and figure out how it gets into a cell and how it moves, we’re going to learn a lot about how cells work.”

Basic research is key to preparing for the next pandemic, as well. “Scientists need to be equipped with all the skills to address these questions when the next SARS comes or the next HIV comes,” Dermody says. “Nobody can tell what the next virus is going to look like … Tomorrow the whole world may be tipped on its ear.”

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