Passive immune protection by herpes simplex virus-specific monoclonal antibodies and monoclonal antibody-resistant mutants altered in pathogenicity.
Virus-neutralizing monoclonal antibodies specific for 13 different genetically defined epitopes of glycoproteins gC, gB, and gD of herpes simplex virus type 1, strain KOS-321, were compared for their ability to provide passive immunity to DBA-2 mice challenged intracranially. Protection was highly specific, since individual monoclonal antibodies failed to protect against infection with monoclonal antibody-resistant (mar) mutants altered in the single epitope recognized by the injected antibody. The dose-response kinetics of passive immunity paralleled the in vitro neutralization titers for each antibody. No correlation was observed between immune protection and antibody isotype or complement-dependent in vitro neutralization titers. This suggests that virus neutralization was not the protective mechanism. In general, antibodies reactive with epitopes of gC were protective at the lowest antibody doses, antibodies specific for gB were less efficient in providing immunity, and antibodies against gD were the least effective. mar mutants with single epitope changes in gC and multiple epitope changes in gB showed highly reduced pathogenicity, requiring up to 5 X 10(6) PFU to kill 50% of infected animals. These findings indicated that antigenic variation affects virus growth and spread in the central nervous system. Thus, mutations which affect antigenic structure also can alter virus pathogenicity. The alteration of these epitopes does not, however, appreciably reduce the development of resistance to infection. Infection of mice with these mutants or inoculation of mice with UV-inactivated, mutant-infected cells before challenge rendered the animals resistant to infection with wild-type herpes simplex virus type 1.
G
G
Kümel
H C
HC
Kaerner
M
M
Levine
C H
CH
Schröder
J C
JC
Glorioso
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes; D006023:Glycoproteins / Q000276:immunology; D006561:Herpes Simplex / Q000517:prevention & control*; D007116:Immunization, Passive; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009154:Mutation; D009500:Neutralization Tests; D018139:Simplexvirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014764:Viral Proteins / Q000276:immunology
D000911:Antibodies, Monoclonal; D000939:Epitopes; D006023:Glycoproteins; D014764:Viral Proteins