A breakthrough on a tropical virus

Scientists at Caltech and Purdue University have determined the fine-detail structure of the virus that causes dengue fever. This advance could lead to new, more focused strategies for devising a vaccine against a viral illness that causes 20,000 deaths each year.

Reporting in the March 8 issue of the journal Cell, Caltech biology professor James Strauss, lead author Richard Kuhn of Purdue (a former postdoctoral scholar in Strauss’s lab), and Michael Rossman and Timothy Baker of Purdue describe the virus’s structure, obtained with a cryoelectron microscope. The detailed electron-density map shows the inner RNA core of the virus, as well as the other spherical layers that cover it. At the surface is the glycoprotein scaffolding thought to allow the virus to interact with the receptor and invade a host cell.

This is the first time the structure of a flavivirus has been described, Strauss says. Flaviviruses are a class of viruses that include the yellow fever, West Nile, tick-borne encephalitis, and Japanese encephalitis viruses. All are enclosed with a glycoprotein outer layer that includes minor projections out of the lipid layer due to the geometry of the scaffolding.

“Most viruses that cause serious illness are enveloped, including influenza, hantaviruses, West Nile virus, smallpox, and herpes—though not polio,” Strauss says.

The surprise for the researchers was the unusual manner in which the glycoproteins are arranged. Details from the Caltech and Purdue computer-generated images show a highly variegated structure of glycoprotein molecules that are evenly dispersed, but with a surprisingly complicated pattern.
“It’s symmetrical, but not with the obvious symmetry of most symmetric viruses,” Strauss explains. “This was not an expected result.”

Strauss says it’s still unclear what the odd symmetry will ultimately mean for future research aimed at controlling the disease, because the precise function of the different structural domains of the glycoproteins are still not known. But a more detailed view of these structures is the beginning of a more informed strategy for a focused medical or pharmaceutical attack, Strauss says. “You can think of the protease inhibitors for HIV. Those in large part came from knowing the structure of the HIV enzymes you were trying to interfere with.”

Thus, the new work could lead to drugs that will bind to the virus to prevent it from entering the cell, or perhaps from reassembling once it is already inside the cell.

Dengue fever is a mosquito-spread disease that has been known for centuries, but was first isolated in the 1940s after it became a significant health concern for American forces in the Pacific theater. A worldwide problem, the disease is found throughout Latin America, the Caribbean, Southeast Asia, and India, and is currently at epidemic levels in Hawaii.

Especially virulent is the closely related dengue hemorrhagic fever, which is responsible for most of the deaths. The disease is a leading cause of infant mortality in Thailand, where there is an especially vigorous program to find an effective vaccine.

More information can be found on the Center for Disease Control Web site at www.cdc.gov/ncidod/dvbid/dengue/index.htm.
•