Antibody-resistant mutations in cross-reactive and type-specific epitopes of herpes simplex virus 1 glycoprotein B map in separate domains

Abstract

To characterize the domains of HSV-1 glycoprotein B (gB), we isolated mutants resistant to monoclonal antibodies with potent neutralizing activity. Partial nucleotide sequencing of the mutations revealed that gB contains two domains comprising discontinuous and continuous amino acids that bind cross-reactive and type-specific neutralizing antibodies. Four mutations in a discontinuous domain, R1435, R233, R1375, and R126, contained substitutions of Tyr 278 for His 278, His 298 for Arg 298, Gln 274 for Arg 274, and Asn 273 for Tyr 273, respectively. Two mutations in a continuous domain, R1392 and R1397, contained substitutions of Thr 32 for Ala 32 and Thr 47 for Asn 47, respectively, and overlapped two other type-specific epitopes. Analysis of the nucleotide sequence of strain KOS showed differences from strain F at four residues proximal to the R1392 mutation and one residue proximal to the R1397 mutation, which explains the failure of HSV-1 (F)-specific antibodies to these epitopes to react with KOS. One target site for proteolytic cleavage of gB by cellular enzymes maps at the amino terminus, partially overlapping four HSV-1-specific epitopes.