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J. Virol. doi:10.1128/JVI.02389-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Natural Mutations in the Receptor Binding Domain of Spike Glycoprotein Determine the Reactivity of Cross-Neutralization between Palm Civet Coronavirus and Severe Acute Respiratory Syndrome Coronavirus

Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016, USA; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Hubei 430071, PRC; AIDS Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, PRC

^* To whom correspondence should be addressed. Email: zchen{at}adarc.org.

	Abstract

The severe acute respiratory syndrome (SARS) outbreak in 2002-2003 occurred as a result of zoonotic transmission. Coronavirus (CoV) found in naturally infected palm civet represents the closest genetic relative to SARS-CoV, but the degree and the determinants of cross-neutralization among these viruses remain to be investigated. Studies indicate that the receptor binding domain (RBD) of SARS-CoV spike (S) glycoprotein contains major determinants for viral entry and neutralization. We aim to characterize the impact of natural mutations within the RBDs of civet-CoVs on viral entry and cross-neutralization. In this study, the S-glycoprotein genes were recovered from naturally infected civets in Central China (Hubei province). This extends the geographic distribution of civet-CoV beyond the Southeastern province of Guangdong. Moreover, pseudoviruses generated in our laboratory with four civet S-genes, each with a distinct RBD, infected cells expressing human receptor angiotensin-converting enzyme-2 but with 90-95% less efficiency compared to SARS-CoV. These four civet S-genes were also constructed as DNA vaccines to immunize mice. Immunized sera elicited against most civet S-glycoproteins displayed potent neutralizing activities against autologous viruses but were much less efficient (IC₅₀, 2040-fold) at neutralizing SARS-CoV, and vice versa. Convalescent sera from humans were similarly ineffective against the dominant civet-pseudovirus. Our findings suggest that the design of SARS vaccine should not only consider the prevention of re-emergence of SARS-CoV, but also provide cross-protection, thus interrupting zoonotic transmission of a group of genetically divergent civet-CoVs of broad geographic origin.

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• Li, F. (2008). Structural Analysis of Major Species Barriers between Humans and Palm Civets for Severe Acute Respiratory Syndrome Coronavirus Infections. J. Virol. 82: 6984-6991 [Abstract] [Full Text]