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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, New York 10016,¹ State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Hubei 430071, People's Republic of China,² AIDS Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China³

Received 31 October 2006/ Accepted 12 February 2007

The severe acute respiratory syndrome (SARS) outbreak of 2002 and 2003 occurred as a result of zoonotic transmission. Coronavirus (CoV) found in naturally infected palm civet (civet-CoV) 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 the 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), extending 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 to 95% less efficiency compared to that of 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 (50% inhibitory concentration, 20- to 40-fold) at neutralizing SARS-CoV and vice versa. Convalescence-phase sera from humans were similarly ineffective against the dominant civet pseudovirus. Our findings suggest that the design of SARS vaccine should consider not only preventing the reemergence of SARS-CoV but also providing cross-protection, thus interrupting zoonotic transmission of a group of genetically divergent civet CoVs of broad geographic origin.

Published ahead of print on 21 February 2007.

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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]