SATURDAY, March 9, 2002 (HealthDayNews) -- For the first time, scientists have mapped the three-dimensional structure of a virus that kills tens of thousands of people every year.
Researchers from California and Indiana have produced a computerized image of the dengue virus, an infectious and potentially deadly member of the flavivirus family. Its cousins include yellow fever and the West Nile virus.
"Flaviviruses are extremely important human pathogens, and we were trying to figure out how do they organize their surface and structure," says Richard Kuhn, the principal investigator of the study, which appeared in yesterday's issue of Cell.
According to Kuhn, an associate professor of biological sciences at Purdue University, previous studies had suggested that flaviviruses have an organized structure in comparison to viruses like HIV or influenza, in which proteins seem to be randomly collected inside a membrane.
"If you know the basic building unit of these viruses, you would be able to figure out the entire virus," Kuhn says.
In order to study the structure of dengue, the researchers needed to concentrate the virus and remove any cellular contaminants that might be present.
Although the strain of dengue virus that the researchers worked with was a slightly weaker version than the wild virus that exists in nature, it's dangerous enough that the virus was grown in sealed containers and handled only inside protective laboratory hoods that prevent it from escaping.
The researchers compiled hundreds of highly detailed, two-dimensional microscopic images of the virus, then fed them through a specialized computer program that produced a three-dimensional model of virus.
The model revealed that dengue has a protective outer protein shell in the shape of a 20-sided sphere.
Viruses like HIV and influenza are known to have proteins that stick off their surface and help the virus attach to a host cell. "When we looked at flaviviruses, it was actually quite different, because the proteins don't stick out," he says. "They actually lie flat, and the surface of the virus is a flat surface."
"Now that we know the structure, we can begin to ask questions of how do the proteins interact with one another," says Kuhn.
Once future genetic and biochemical studies are completed, he adds, it may be possible to design molecules that might interfere with certain functions of the virus. "These would be antivirals that would block the assembly of the virus," Kuhn says.
At the same time, the flavivirus surface differed in another crucial way. While portions of a structure known as the lipid bilayer, which lies between the protein shell and the virus's genetic material, are usually visible on other viruses, the dengue virus' protein shell covered the entire bilayer.
"[It's] really unusual," Kuhn says. Since the bilayer must fuse with the host cell membrane in order for the virus to get into the cell, the shell must rearrange itself dramatically at some point during the virus's life cycle, he adds.
The researchers are currently studying how this might happen. "Knowing that kind of information, we can think about designing agents that will block those processes," says Kuhn.
The public health impact of dengue virus in Asia and Central and South America makes these findings significant, according to another expert in flaviviruses.
"Dengue virus is one of the major pathogens, affecting over 100 million people every year," says Radhakris Padmanabhan, a professor of biochemistry and molecular biology at the University of Kansas Medical Center in Kansas City.
"There is no antiviral drug against a dengue virus infection," he adds. "It causes dengue fever, dengue hemorrhagic fever and dengue shock syndrome, and this is a major problem in tropical and sub-tropical areas of the world."
"Knowing the structure of the flavivirus opens a lot of doors for developing antiviral drugs," Padmanabhan says. "This is a great start for developing a drug which can prevent the attachment of the virus to the host cell."
But since the related flavivirus known as West Nile virus, which can cause severe inflammation of the brain and spinal cord in humans, surfaced in North America in 1999, the problem seems much closer to home.
"Although West Nile is not as significant a pathogen to humans as dengue virus is, there's still concern and there's still people that get sick from it," says Kuhn. "There is a need for developing vaccines and for developing antivirals against the flaviviruses, because the flaviviruses represent very significant human pathogens."
Kuhn estimates that tests of antiviral compounds for dengue on laboratory cell cultures could occur within five years, although it will take longer to progress to human trials.
What To Do: Find out more about dengue from the Centers for Disease Control and Prevention, the World Health Organization or Health Canada.
