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Journal of Virology, October 2007, p. 10804-10814, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00999-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Single Amino Acid Changes in the Nipah and Hendra Virus Attachment Glycoproteins Distinguish EphrinB2 from EphrinB3 Usage{triangledown}

Oscar A. Negrete,1 David Chu,1 Hector C. Aguilar,1 and Benhur Lee1,2,3*

Department of Microbiology, Immunology and Molecular Genetics,1 Department of Pathology and Laboratory Medicine,2 UCLA AIDS Institute, UCLA, Los Angeles, California 900953

Received 8 May 2007/ Accepted 29 June 2007

The henipaviruses, Nipah virus (NiV) and Hendra virus (HeV), are lethal emerging paramyxoviruses. EphrinB2 and ephrinB3 have been identified as receptors for henipavirus entry. NiV and HeV share similar cellular tropisms and likely use an identical receptor set, although a quantitative comparison of receptor usage by NiV and HeV has not been reported. Here we show that (i) soluble NiV attachment protein G (sNiV-G) bound to cell surface-expressed ephrinB3 with a 30-fold higher affinity than that of sHeV-G, (ii) NiV envelope pseudotyped reporter virus (NiVpp) entered ephrinB3-expressing cells much more efficiently than did HeV pseudotyped particles (HeVpp), and (iii) NiVpp but not HeVpp entry was inhibited efficiently by soluble ephrinB3. These data underscore the finding that NiV uses ephrinB3 more efficiently than does HeV. Henipavirus G chimeric protein analysis implicated residue 507 in the G ectodomain in efficient ephrinB3 usage. Curiously, alternative versions of published HeV-G sequences show variations at residue 507 that can clearly affect ephrinB3 but not ephrinB2 usage. We further defined surrounding mutations (W504A and E505A) that diminished ephrinB3-dependent binding and viral entry without compromising ephrinB2 receptor usage and another mutation (E533Q) that abrogated both ephrinB2 and -B3 usage. Our results suggest that ephrinB2 and -B3 binding determinants on henipavirus G are distinct and dissociable. Global expression analysis showed that ephrinB3, but not ephrinB2, is expressed in the brain stem. Thus, ephrinB3-mediated viral entry and pathology may underlie the severe brain stem neuronal dysfunction seen in fatal Nipah viral encephalitis. Characterizing the determinants of ephrinB2 versus -B3 usage will further our understanding of henipavirus pathogenesis.

* Corresponding author. Mailing address: Department of Microbiology, Immunology and Molecular Genetics, UCLA, 609 Charles Young Dr., 3825 Molecular Science Building, Los Angeles, CA 90095. Phone: (310) 794-2132. Fax: (310) 267-2580. E-mail: bleebhl{at}ucla.edu

{triangledown} Published ahead of print on 25 July 2007.

Journal of Virology, October 2007, p. 10804-10814, Vol. 81, No. 19
0022-538X/07/$08.00+0     doi:10.1128/JVI.00999-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Aguilar, H. C., Ataman, Z. A., Aspericueta, V., Fang, A. Q., Stroud, M., Negrete, O. A., Kammerer, R. A., Lee, B. (2009). A Novel Receptor-induced Activation Site in the Nipah Virus Attachment Glycoprotein (G) Involved in Triggering the Fusion Glycoprotein (F). J. Biol. Chem. 284: 1628-1635 [Abstract] [Full Text]  
  • Xu, K., Rajashankar, K. R., Chan, Y.-P., Himanen, J. P., Broder, C. C., Nikolov, D. B. (2008). Host cell recognition by the henipaviruses: Crystal structures of the Nipah G attachment glycoprotein and its complex with ephrin-B3. Proc. Natl. Acad. Sci. USA 105: 9953-9958 [Abstract] [Full Text]  


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