Dengue virus E envelop glycoprotein
The dengue virus (DENV) is a mosquito-borne member of the flavivirus genus responsible for roughly 50 million human infections each year. DENV is composed of four distinct but serologically related flaviviruses, which circulate in tropical and subtropical regions of the globe. Infection by any of the four DENV serotypes may cause a self-limiting febrile illness that is rarely fatal, and is thought to confer immunity to reinfection by the same serotype of DENV.
Although DENV infection induces lifelong immunity against viruses of the same serotype, the antibodies raised appear to contribute to severe disease in cases of heterotypic infections, including hemorrhage and shock. Understanding the mechanisms of DENV neutralization by antibodies is, therefore, crucial for the design of vaccines that simultaneously protect against all four viruses and is critical for understanding factors that contribute to pathogenesis.
We report a comparative, high-resolution crystallographic analysis of an ‘‘A-strand’’ murine monoclonal antibody, Mab 4E11, in complex with its target domain 3 of the envelope glycoprotein E from the four DENV serotypes. Mab 4E11 is capable of neutralizing all four serotypes, and our study reveals the determinants of this cross-reactivity. The structures also highlight the mechanism by which A-strand Mabs disrupt the architecture of the mature virion, inducing premature fusion loop exposure and concomitant particle inactivation.
Structure of DENV-1 Domain 3 (in blue) in complex with scFv 4E11.
The heavy-/light-chain framework regions of scFv 4E11 are dark/light gray, respectively.
The CDR loops of scFv 4E11 are labeled H1, H2, H3 (orange, cyan, pink) and L1, L2, L3 (yellow, green, dark pink).
Mechanism of Dengue Virus Broad Cross-Neutralization by a Monoclonal Antibody. Cockburn JJ, Navarro Sanchez ME, Fretes N, Urvoas A, Staropoli I, Kikuti CM, Coffey LL, Arenzana Seisdedos F, Bedouelle H, Rey FA. Structure. 2012 Feb 8;20(2):303-14.
This work was funded in main part by the Pediatric Dengue Vaccine Initiative (PDVI). Fundings came alsofrom the French ‘Agence Nationale de la Recherche’ (ANR, DENtry, program ‘Microbiologie, Infections et Immunité’), from Merck-Serono and by recurrent fundings from Institut Pasteur and CNRS. C.J.J. was supported by an EMBO Long-Term fellowship (ALTF-194-2005), by a Marie Curie Intra European fellowship and by the Institut Pasteur ‘Programme Transversal de Recherche’ (InhibViro, PTR n°338) fellowship. B.H. was funded by the French Ministry of Defense (DGA Nos 04.34.025 and 01.34.062) and the European Union (FP6-2003-INCO-DEV2 N° 517711 ‘DEANFRAME’).
Press release (in english) (in french)
Previews: ’Capturing a Virus while it Catches its Breath’ by Theodore C. Pierson and Richard J. Kuhn.
Structure. 2012 Feb 8;20(2):200-202.