Molecular analysis of the immune response to human cytomegalovirus glycoprotein B (gB). II. Low gB-specific T and B cell responses are associated with expression of certain HLA-DR alleles.

Human cytomegalovirus (HCMV) is a common cause of congenital infection leading to birth defects and a leading cause of serious illness in patients with immunodeficiencies. Studies in this laboratory have focused on a molecular analysis of the immune response to glycoprotein B (gB) of HCMV. This protein has been shown to elicit B cell, helper T cell (Th), and cytotoxic T cell responses, suggesting that it may be useful as a subunit HCMV vaccine. However, previous studies showed that although peripheral blood mononuclear cells (PBMC) from all HCMV-seropositive donors proliferate in response to stimulation with whole HCMV, not all donors respond to purified recombinant gB. In the present study, PBMC from HCMV-seropositive donors homozygous for HLA-DR were tested for proliferative responses to whole HCMV and to purified gB expressed in vaccinia virus. PBMC from all donors proliferated in response to HCMV, but those from multiple donors expressing the HLA-DR3Dw3 and -DR4Dw4 specificities, and single donors expressing the -DR15Dw2, -DR13Dw19 and -DR14Dw9 specificities, failed to respond to gB. These results suggested a possible HLA-DR association with low proliferative responses to gB. In further studies, PBMC from donors expressing both putative gB-high responder and low responder HLA-DR alleles were stimulated multiple times with gB to generate gB-specific T cell lines. These cells were then tested for proliferative responses to gB presented by irradiated PBMC sharing only one DR allele with the responder cells. Cells from the gB-specific lines proliferated only when antigen was presented in the context of a responder DR allele but not when presented in the context of a low responder DR allele. Analysis of immune sera revealed that those from donors with PBMC proliferative responses always contained antibodies reactive with B cell epitopes on both the N-terminal gp93 and C-terminal gp55 portions of gB. In contrast, many of the sera from donors with low gB-specific proliferative responses had gp55-specific antibodies but lacked antibodies to gp93. These results suggest that immunogenetic differences in Th responsiveness to gB may lead to lack of antigen-specific help for antibody responses to gp93 in some cases. The prevalence of these low responder HLA alleles in the population, and the central importance of the T cell response to the generation of antibodies suggest that native gB alone may not be an attractive candidate for an HCMV subunit vaccine.