Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein.

Abstract

Rabies virus (RABV) causes fatal encephalitis in more than 59,000 people yearly. Upon the bite of an infected animal, the development of clinical disease can be prevented with post-exposure prophylaxis (PEP), which includes the administration of Rabies immunoglobulin (RIG). However, the high cost and limited availability of serum-derived RIG severely hamper its wide use in resource-limited countries. A safe low-cost alternative is provided by using broadly neutralizing monoclonal antibodies (bnAbs). Here we report the X-ray structure of one of the most potent and most broadly reactive human bnAbs, RVC20, in complex with its target domain III of the RABV glycoprotein (G). The structure reveals that the RVC20 binding determinants reside in a highly conserved surface of G, rationalizing its broad reactivity. We further show that RVC20 blocks the acid-induced conformational change required for membrane fusion. Our results may guide the future development of direct antiviral small molecules for Rabies treatment.

• Authors: Jan Hellert, Julian Buchrieser, Florence Larrous, Andrea Minola, Guilherme Dias de Melo, Leah Soriaga, Patrick England, Ahmed Haouz, Amalio Telenti, Olivier Schwartz, Davide Corti, Hervé Bourhy, Félix A Rey
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 596 (01 30 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32001700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Antibodies, Viral
• Epitopes
• Glycoproteins
• Viral Proteins

Topics

• Amino Acid Sequence
• Animals
• Antibodies, Neutralizing (chemistry)
• Antibodies, Viral (chemistry)
• Antibody Affinity
• Cell Line
• Crystallography, X-Ray
• Epitopes (genetics)
• Glycoproteins (metabolism)
• Humans
• Mutagenesis (genetics)
• Perfusion
• Protein Binding
• Rabies virus (immunology)
• Viral Proteins (metabolism)