New class of virus changes shape during infection

Teams of researchers discovered the binding of a viral RNA and a viral protein brings about a physical transformation duping host cells into copying the invading pathogen.

The discovery opens up a new angle of attack in which to treat these infections. Differences in the cellular and flavivirus RNA's are a basis for a drug treatment and eventually a vaccine for these flaviviruses that affect just over one third of the world's population.

The Harvard-MIT Division of Health Sciences and Technology mapped the 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 relatives include flaviviruses that cause dengue fever, Japanese encephalitis and West Nile disease.

They discovered during infection, 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. 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.

The structure highlights one end of the viral RNA that the host cell's replicating enzyme attaches to and begins making more copies of the infecting virus.

Ordinarily, the translation of viral RNA into protein is triggered by an RNA building block, adenosine, at one end of the RNA that flaviviruses lack. AMV substitutes this RNA-protein complex.

Dengue fever is a disease in which no major discovery effort has been directed to new treatments despite figures that suggest that it is long overdue. The World Health Organisation (WHO) cites 58,000 new cases of dengue fever in Indonesia alone during 2004 leading to 650 deaths. Worldwide, there are about 500,000 hospitalisations to treat dengue patients each year.

The team, led by professor Lee Gehrke, intend to 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 research underlies the need for an effective treatment for these diseases, most of which are neglected research-wise. At present only supportive treatment for dengue fever patients is available. Antiviral medications offer much and advances in genetic research are aiding their development.

One particular area of promise is Acambis' ChimeriVax-Dengue vaccine. The "tetravalent" vaccine has shown in advanced pre-clinical trials to induce high levels of protective antibodies against all four dengue virus serotypes. There were no serious adverse events reported.

The research features in the December 17 issue of Science​