Paris, February 10, 2012

Newly characterized dengue virus antibody shows promise

Research teams from the Institut Pasteur, the CNRS, and Inserm have recently characterized the structure and mechanism of action of an antibody that successfully neutralizes all four strains of the dengue virus in mice models. Their groundbreaking work represents major progress for research efforts that hope to develop an effective vaccine to combat this disease. This study was published February 8, 2012 in the scientific journal Structure.


The variation represented in the dengue virus’ four distinct strains makes vaccine development a complicated task. These strains, called serotypes, are each characterized by their own specific and unique properties. Scientists have already shown that an individual immune to any of the four strains increases his/her risk, not only of being infected by the other three strains, but also of developing severe life-threatening forms of this disease. This is why researchers need to develop a vaccine or treatment that targets all four serotypes.

Research teams from the Institut Pasteur, the CNRS, and Inserm, led by Félix Rey* and Hugues Bedouelle** (Institut Pasteur/CNRS), have, for the first time, succeeded in characterizing an antibody capable of neutralizing all four strains of the dengue virus in mice models. By using comparative analyses and high-resolution crystallography, Félix Rey’s team was able to visualize the way the antibody binds to the virus on the specific recognition sites of each strain.

The teams also showed that the antibody recognizes the surface protein of the virus with varying affinities and neutralization potencies according to the viral serotype (1, 2, 3 or 4), but that the neutralization mechanism is the same in each case. It involves irreversible disruption of the virus particle, rendering it harmless.

These results provide a novel molecular basis for understanding antibody neutralization of the four dengue viruses, and will undoubtedly help to design a safe, protective vaccine.


Financing for this work was provided by the Merck Serono chair, the French National Research Agency (ANR), the EMBO Long Term Fellowship, the French Ministry of Defense, and DENFRAME, the European program for dengue research.

* Félix Rey, head of the Structural Virology Unit (Institut Pasteur / CNRS URA 3015),
** Hugues Bedouelle, Molecular Prevention and Therapy of Human Diseases Unit (Institut Pasteur / CNRS URA 3012)


Dengue

Dengue is a viral infection common in tropical regions that is transmitted by mosquitoes within the Aedes genus. Symptoms include high fever and headache and in severe cases the virus may develop into life-threatening dengue hemorrhagic fever or dengue shock syndrome. The WHO estimates that up to 50 million people are affected by this disease each year. Because there are currently no vaccines or treatments available for this disease the only recourse left to fight infection are population control of vector mosquitoes in affected areas and individual mosquito protection.
Today dengue is considered an immerging disease as a result of the rising number of cases and its spread to areas that are normally unaffected. The first cases of dengue in mainland France were reported in September 2010.
 
For more information about dengue research at the Institut Pasteur, visit our online page (French version only) at  http://www.pasteur.fr/ip/easysite/pasteur/fr/presse/fiches-sur-les-maladies-infectieuses/dengue


Source

Mechanism of dengue virus broad cross-neutralization by a monoclonal antibody, Structure, published February 8, 2012

Joseph J. B. Cockburn1,2, M. Erika Navarro Sanchez1,2, Nickolas Fretes1,2, Agathe Urvoas3,4, Isabelle Staropoli5,6, Carlos M. Kikuti1,2, Lark L. Coffey7,8, Fernando Arenzana Seisdedos5,6, Hugues Bedouelle3,4, and Felix A. Rey1,2

1 Institut Pasteur, Unité de Virologie Structurale, Département de Virologie, 75724 Paris Cedex 15, France
2 CNRS, URA3015, 75724 Paris Cedex 15, France
3 Institut Pasteur, Unité de Recherche Prévention et Thérapie Moléculaires des Maladies Humaines, Département d’Infection et Epidémiologie, 75724 Paris Cedex 15, France
4 CNRS, URA3012, 75724 Paris Cedex 15, France
5 Institut Pasteur, Unité de Pathogénie Virale, Département de Virologie, 75724 Paris Cedex 15, France
6 INSERM, U819, 75724 Paris Cedex 15, France
7 Groupe à 5 ans Populations Virales et Pathogenèse, Département de Virologie, 75724 Paris Cedex 15, France
8 CNRS, URA3015, 75724 Paris Cedex 15, France


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