Key stage to dengue fever replication found

11 August 2006

The discovery that the dengue fever virus needs to bend into a circle in order to replicate suggests new ways to treat this and similar diseases, including West Nile virus and encephalitis, say researchers. Future drugs that prevent the virus from forming a ring shape could one day save thousands of lives, they add.

"The challenge now is to see if we can design a small molecule to do the job," says Andrea Gamarnik at the Leloir Institute in Buenos Aires, Argentina.

There are about 50 million cases of dengue fever globally each year, the World Health Organisation estimates. The virus is spread through the bite of the Aedes aegypti mosquito and claims around 25,000 lives each year, many of them children. There is no treatment or vaccine available for the disease, which is dubbed 'break-bone fever' due to the terrible pain it inflicts.

Gamarnik and her colleagues say they have found the key to the virus's replication-and that this could be its Achilles' heel.

It was discovered only recently that the virus, made of RNA, can change its shape from a long strand into a circle. It is able to do so thanks to special, short sequences on the ends of the strands that attract one another, acting like 'sticky tape', according to the researchers. But the importance of this shape was not clear.

Promoter region
Now Gamarnik has discovered that the particular viral enzyme required to replicate the virus is only able to recognise a ring-shaped structure. When the dengue strand forms a circle, proteins can latch on to the 'promoter' region at the joined ends of the strand and, crucially, go on from there to replicate the virus, Gamarnik explains.

The team tested their theory using animal cells. When the sticky ends of the strand were modified not to match, the virus failed to replicate in mosquito or hamster cells. However, when these modified ends were re-engineered to attract one another again in a new way, the virus succeeded in replicating within the cells.

The new findings should encourage researchers to look for molecules that either block the sticky ends from attaching or block the protein from binding to the promoter region, says Gamarnik. She believes such molecules could one day serve as powerful drugs to treat patients with dengue fever.

And Gamarnik adds that other illnesses, such as West Nile disease, caused by the same group of viruses as Dengue fever, known as 'flaviviruses', may be tackled with a similar approach. She says that West Nile virus appears, for example, to have similar sticky ends, though no one has yet shown it adopting a circular shape to replicate.

(Source: Genes and Development: Leloir Institute: August 2006).