Escape from human monoclonal antibody neutralization affects in vitro and in vivo fitness of severe acute respiratory syndrome coronavirus.
BACKGROUND
Severe acute respiratory syndrome (SARS) emerged as a human disease in 2002. Detailed phylogenetic analysis and epidemiologic studies have suggested that the SARS coronavirus (SARS-CoV) originated from animals. The spike (S) glycoprotein has been identified as a major target of protective immunity and contains 3 regions that are targeted by neutralizing antibodies in the S1 and S2 domains. We previously characterized a panel of neutralizing human monoclonal antibodies (MAbs), but the majority of epitopes recognized by the MAbs remain unknown.


METHODS
In the present study, we generated neutralization escape mutants and studied the effect of these neutralization escape mutations on human and animal receptor usage as well as on in vitro and in vivo fitness.


RESULTS
Distinct but partially overlapping sets of amino acids were identified that are critical to the binding of MAbs with differential neutralization profiles. We also identified possible interactions between the S1 and S2 domains of the SARS-CoV S glycoprotein. Finally, we showed that escape from neutralization usually attenuates SARS-CoV infection.


CONCLUSIONS
These data provide a mechanism for overcoming neutralization escape by use of broadly cross-reactive cocktails of cross-neutralizing MAbs that recognize residues within the receptor-binding domain that are critical for virus replication and virulence.
Departments of 1Epidemiology and Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 57599, USA. rbaric@email.unc.edu
Barry
B
Rockx
Eric
E
Donaldson
Matthew
M
Frieman
Timothy
T
Sheahan
Davide
D
Corti
Antonio
A
Lanzavecchia
Ralph S
RS
Baric
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D000914:Antibodies, Viral / Q000276:immunology; D002460:Cell Line; D005260:Female; D006801:Humans; D008168:Lung / Q000473:pathology / Q000821:virology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009500:Neutralization Tests; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy / Q000821:virology; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D008562:Membrane Glycoproteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; C578557:spike glycoprotein, SARS-CoV