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J. Virol. doi:10.1128/JVI.00999-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Single amino acid changes in the Nipah and Hendra virus attachment glycoprotein distinguishes ephrinB2 from ephrinB3 usage

Department of Microbiology, Immunology and Molecular Genetics, Department of Pathology and Laboratory Medicine, UCLA AIDS Institute, UCLA, Los Angeles, CA, USA 90095

^* To whom correspondence should be addressed. Email: bleebhl{at}ucla.edu.

	Abstract

The henipaviruses, Nipah (NiV) and Hendra (HeV) viruses 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 (1) soluble NiV attachment protein G (sNiV-G) bound to cell surface expressed ephrinB3 with 30-fold higher affinity than sHeV-G, (2) that NiV envelope pseudotyped reporter virus (NiVpp) entered ephrinB3 expressing cells much more efficiently than HeV pseudotyped particles (HeVpp), and (3) that NiVpp, but not HeVpp, entry was inhibited efficiently by soluble ephrinB3. These data underscore that NiV uses ephrinB3 more efficiently than 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 B2 usage. We further define surrounding mutations (W504A and E505A) that diminished ephrinB3-dependent binding and viral entry without compromising ephrinB2 receptor usage, and another (E533Q) that abrogated both ephrinB2 and B3 usage. Our results suggest ephrinB2 and B3 binding determinants on henipavirus G are distinct and dissociable. Global expression analysis shows 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 encephalitis. Characterizing the determinants of ephrinB2 versus B3 usage will further our understanding of henipavirus pathogenesis.

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