Emerging Class Of Viruses Found To Change Shape To Infect Humans

In the December 17 issue of Science, collaborators led by professor Lee Gehrke of the Harvard-MIT Division of Health Sciences and Technology publish dramatic three-dimensional images of RNA-protein interactions in alfalfa mosaic virus (AMV), a safe model for investigating single-strand, positive-sense RNA viruses. AMV's dangerous relatives include flaviviruses that cause dengue fever, Japanese encephalitis and West Nile disease.

Gehrke and other molecular virologists knew that AMV was not infectious unless its genomic RNAs bound viral protein, but the details were unknown. Laura Guogas, a graduate student in Gehrke's lab, decided to seek answers with x-ray crystallography.

What Guogas found is "stunning and unexpected," says James Hogle, an structural biologist and professor of biological chemistry and molecular pharmacology at Harvard Medical School. He and David Filman, also of HMS, contributed to this study.<

RNA binding turned the viral coat protein from a floppy coil into a tight, springy helix. The RNA, a smooth strand punctuated by bumpy "hairpin structures," developed a kink that looks like a mountain turn on the Tour de France. The researchers attribute this kink to the formation of additional links between the two sides of the hairpins, another surprise from the three-dimensional structure. RNA and protein fold together in a way that locks them into place.

This distinctive, stable structure turns one end of the viral RNA into a handsome stranger. "It sticks out like a beacon compared with other RNAs in the cell," says Gehrke, who proposes that the host cell's replicating enzyme "jumps right on" and begins making more copies of the infecting virus.

Ordinarily, the translation of viral RNA into protein is triggered by a string of a particular RNA building block, adenosine, at one end of a typical RNA, a so-called "poly-A tail" that flaviviruses lack. AMV substitutes the striking RNA-protein complex that Guogas identified; other viruses in the family probably form different structures that make the ends of their RNA attractive to the cell's replicating machinery.

Future research will look for ways to translate differences between cellular and flavivirus RNAs into vaccines and treatments for dengue fever, West Nile virus, and similar emerging infections. The researchers hope to build on the synergy between biochemistry and structural biology demonstrated by Guogas's study. "This project is a great example of the role a talented student can play in a collaboration between two labs with complementary interests and expertise," says Hogle.