title: Distinct mechanisms of neutralization by monoclonal antibodies specific for sites in the N-terminal or C-terminal domain of murine leukemia virus SU.
abstract: The epitope specificities and functional activities of monoclonal antibodies (MAbs) specific for the murine leukemia virus (MuLV) SU envelope protein subunit were determined. Neutralizing antibodies were directed towards two distinct sites in MuLV SU: one overlapping the major receptor-binding pocket in the N-terminal domain and the other involving a region that includes the most C-terminal disulfide-bonded loop. Two other groups of MAbs, reactive with distinct sites in the N-terminal domain or in the proline-rich region (PRR), did not neutralize MuLV infectivity. Only the neutralizing MAbs specific for the receptor-binding pocket were able to block binding of purified SU and MuLV virions to cells expressing the ecotropic MuLV receptor, mCAT-1. Whereas the neutralizing MAbs specific for the C-terminal domain did not interfere with the SU-mCAT-1 interaction, they efficiently inhibited cell-to-cell fusion mediated by MuLV Env, indicating that they interfered with a postattachment event necessary for fusion. The C-terminal domain MAbs displayed the highest neutralization titers and binding activities. However, the nonneutralizing PRR-specific MAbs bound to intact virions with affinities similar to those of the neutralizing receptor-binding pocket-specific MAbs, indicating that epitope exposure, while necessary, is not sufficient for viral neutralization by MAbs. These results identify two separate neutralization domains in MuLV SU and suggest a role for the C-terminal domain in a postattachment step necessary for viral fusion.
authors.affiliation: Laboratory of Retroviral Biology, Public Health Research Institute, Newark, New Jersey 07103-3535, USA.
authors.forename: Michael Dominic
authors.initials: MD
authors.lastname: Burkhart
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Kayman
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
authors.forename: Abraham
authors.initials: A
authors.lastname: Pinter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics; D001665:Binding Sites; D002460:Cell Line; D006224:Cricetinae; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000235:genetics; D005622:Friend murine leukemia virus / Q000235:genetics / Q000276:immunology; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D017434:Protein Structure, Tertiary; D051381:Rats; D011991:Receptors, Virus / Q000276:immunology; D015682:Retroviridae Proteins, Oncogenic / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000956:Antigens, Viral; D000939:Epitopes; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; D015682:Retroviridae Proteins, Oncogenic; D014759:Viral Envelope Proteins; C070506:ecotropic murine leukemia virus receptor