title: The context of gene expression defines the immunodominance hierarchy of cytomegalovirus antigens.
abstract: Natural immunity to CMV dominates the CD4 and CD8 memory compartments of the CMV-seropositive host. This property has been recently exploited for experimental CMV-based vaccine vector strategies, and it has shown promise in animal models of AIDS and Ebola disease. Although it is generally agreed that CMV-based vaccine vectors may induce highly protective and persistent memory T cells, the influence of the gene expression context on Ag-specific T cell memory responses and immune protection induced by CMV vectors is not known. Using murine CMV (MCMV) recombinants expressing a single CD8 T cell epitope from HSV-1 fused to different MCMV genes, we show that magnitude and kinetics of T cell responses induced by CMV are dependent on the gene expression of CMV Ags. Interestingly, the kinetics of the immune response to the HSV-1 epitope was paralleled by a reciprocal depression of immune responses to endogenous MCMV Ags. Infection with a recombinant MCMV inducing a vigorous initial immune response to the recombinant peptide resulted in a depressed early response to endogenous MCMV Ag. Another recombinant virus, which induced a slowly developing "inflationary" T cell response to the HSV-1 peptide, induced weaker long-term responses to endogenous CMV Ags. Importantly, both mutants were able to protect mice from a challenge with HSV-1, mediating strong sterilizing immunity. Our data suggest that the context of gene expression markedly influences the T cell immunodominance hierarchy of CMV Ags, but the immune protection against HSV-1 does not require inflationary CD8 responses against the recombinant CMV-expressed epitope.
authors: Department of Vaccinology, Helmholtz Center for Infection Research, Braunschweig 38124, Germany.
authors: Iryna
authors: I
authors: Dekhtiarenko
authors: Michael A
authors: MA
authors: Jarvis
authors: Zsolt
authors: Z
authors: Ruzsics
authors: Luka
authors: L
authors: Čičin-Šain
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D015870:Gene Expression; D023061:Gene Order; D016679:Genome, Viral; D006561:Herpes Simplex / Q000276:immunology / Q000517:prevention & control; D018259:Herpesvirus 1, Human / Q000276:immunology; D016056:Immunodominant Epitopes / Q000235:genetics* / Q000276:immunology*; D008297:Male; D051379:Mice; D018146:Muromegalovirus / Q000235:genetics* / Q000276:immunology*; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D014779:Virus Replication
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D010455:Peptides