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Journal of Virology, May 2006, p. 4878-4889, Vol. 80, No. 10
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.10.4878-4889.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

N-Glycans on Nipah Virus Fusion Protein Protect against Neutralization but Reduce Membrane Fusion and Viral Entry

Hector C. Aguilar,1 Kenneth A. Matreyek,1 Claire Marie Filone,2 Sara T. Hashimi,1 Ernest L. Levroney,1 Oscar A. Negrete,1 Andrea Bertolotti-Ciarlet,2 Daniel Y. Choi,1 Ian McHardy,1 Jennifer A. Fulcher,3 Stephen V. Su,1 Mike C. Wolf,1 Luciana Kohatsu,3 Linda G. Baum,3 and Benhur Lee1,3,4*

Department of Microbiology, Immunology and Molecular Genetics,1 Department of Pathology and Laboratory Medicine,3 AIDS Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90095,4 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 191042

Received 19 December 2005/ Accepted 28 February 2006

Nipah virus (NiV) is a deadly emerging paramyxovirus. The NiV attachment (NiV-G) and fusion (NiV-F) envelope glycoproteins mediate both syncytium formation and viral entry. Specific N-glycans on paramyxovirus fusion proteins are generally required for proper conformational integrity and biological function. However, removal of individual N-glycans on NiV-F had little negative effect on processing or fusogenicity and has even resulted in slightly increased fusogenicity. Here, we report that in both syncytium formation and viral entry assays, removal of multiple N-glycans on NiV-F resulted in marked increases in fusogenicity (>5-fold) but also resulted in increased sensitivity to neutralization by NiV-F-specific antisera. The mechanism underlying the hyperfusogenicity of these NiV-F N-glycan mutants is likely due to more-robust six-helix bundle formation, as these mutants showed increased fusion kinetics and were more resistant to neutralization by a fusion-inhibitory reagent based on the C-terminal heptad repeat region of NiV-F. Finally, we demonstrate that the fusogenicities of the NiV-F N-glycan mutants were inversely correlated with the relative avidities of NiV-F's interactions with NiV-G, providing support for the attachment protein "displacement" model of paramyxovirus fusion. Our results indicate that N-glycans on NiV-F protect NiV from antibody neutralization, suggest that this "shielding" role comes together with limiting cell-cell fusion and viral entry efficiencies, and point to the mechanisms underlying the hyperfusogenicity of these N-glycan mutants. These features underscore the varied roles that N-glycans on NiV-F play in the pathobiology of NiV entry but also shed light on the general mechanisms of paramyxovirus fusion with host cells.

* Corresponding author. Mailing address: Department of MIMG, 3825 MSB, 609 Charles E. Young Drive East, UCLA, Los Angeles, CA 90095. Phone: (310) 206-8792. Fax: (310) 267-2580. E-mail: bleebhL{at}ucla.edu.

Journal of Virology, May 2006, p. 4878-4889, Vol. 80, No. 10
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.10.4878-4889.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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