Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses.
Molecular characterization of the severe acute respiratory syndrome coronavirus has revealed genetic diversity among isolates. The spike (S) glycoprotein, the major target for vaccine and immune therapy, shows up to 17 substitutions in its 1,255-aa sequence; however, the biologic significance of these changes is unknown. Here, the functional effects of S mutations have been determined by analyzing their affinity for a viral receptor, human angiotensin-converting enzyme 2 (hACE-2), and their sensitivity to Ab neutralization with viral pseudotypes. Although minor differences among eight strains transmitted during human outbreaks in early 2003 were found, substantial functional changes were detected in S derived from a case in late 2003 from Guangdong province [S(GD03T0013)] and from two palm civets, S(SZ3) and S(SZ16). S(GD03T0013) depended less on the hACE-2 receptor and was markedly resistant to Ab inhibition. Unexpectedly, Abs that neutralized most human S glycoproteins enhanced entry mediated by the civet virus S glycoproteins. The mechanism of enhancement involved the interaction of Abs with conformational epitopes in the hACE-2-binding domain. Finally, improved immunogens and mAbs that minimize this complication have been defined. These data show that the entry of severe acute respiratory syndrome coronaviruses can be enhanced by Abs, and they underscore the need to address the evolving diversity of this newly emerged virus for vaccines and immune therapies.
Yang
Zhi-yong
ZY
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005, 40 Convent Drive, Bethesda, MD 20892-3005, USA.
Werner
Heidi C
HC
Kong
Wing-pui
WP
Leung
Kwanyee
K
Traggiai
Elisabetta
E
Lanzavecchia
Antonio
A
Nabel
Gary J
GJ
D000085962:Angiotensin-Converting Enzyme 2; D000914:Antibodies, Viral / Q000276:immunology* / Q000494:pharmacology; D000940:Antigenic Variation / Q000235:genetics; D002268:Carboxypeptidases / Q000276:immunology; D045744:Cell Line, Tumor; D004196:Disease Outbreaks; D000939:Epitopes; D014644:Genetic Variation / Q000276:immunology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D020125:Mutation, Missense; D007703:Peptidyl-Dipeptidase A; D011991:Receptors, Virus; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000276:immunology*; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000276:immunology
D000914:Antibodies, Viral; D000939:Epitopes; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2