Abstract
In common with other herpes viruses, bovine herpes virus 1 (BHV-1) induces strong virus-specific CD8 T-cell responses. However, there is a paucity of information on the antigenic specificity of the responding T-cells. The development of a system to generate virus-specific CD8 T-cell lines from BHV-1-immune cattle, employing Theileria-transformed cell lines for antigen presentation, has enabled us to address this issue. Use of this system allowed the study to screen for CD8 T-cell antigens that are efficiently presented on the surface of virus-infected cells. Screening of a panel of 16 candidate viral gene products with CD8 T-cell lines from 3 BHV-1-immune cattle of defined MHC genotypes identified 4 antigens, including 3 immediate early (IE) gene products (ICP4, ICP22 and Circ) and a tegument protein (UL49). Identification of the MHC restriction specificities revealed that the antigens were presented by two or three class I MHC alleles in each animal. Six CD8 T-cell epitopes were identified in the three IE proteins by screening of synthetic peptides. Use of an algorithm (NetMHCpan) that predicts the peptide-binding characteristics of restricting MHC alleles confirmed and, in some cases refined, the identity of the epitopes. Analyses of the epitope specificity of the CD8 T-cell lines showed that a large component of the response is directed against these IE epitopes. The results indicate that these IE gene products are dominant targets of the CD8 T-cell response in BHV-I-immune cattle and hence are prime-candidate antigens for the generation of a subunit vaccine.
Highlights
Infection with herpes viruses typically results in an acute lytic phase of virus replication, which may be associated with clinical symptoms, followed by establishment of latent infection that can persist for many years
The results indicate that these immediate early (IE) gene products are dominant targets of the CD8 T-cell response in BHV-I-immune cattle and are prime-candidate antigens for the generation of a subunit vaccine
The prominent role of CD8 T cells in immunity is consistent with the capacity of herpesviruses, including bovine herpes virus 1 (BHV-1), to inhibit a number of the steps involved in processing and presentation of antigen to CD8 T cells [3, 4], reducing the efficiency of the CD8 T-cell response
Summary
Infection with herpes viruses typically results in an acute lytic phase of virus replication, which may be associated with clinical symptoms, followed by establishment of latent infection that can persist for many years. Infected cells express only a few genes, but reactivation can occur, often triggered by stress or immunosuppression, whereby expression of the full complement of viral genes is restored, resulting in the production of infectious virus. The prominent role of CD8 T cells in immunity is consistent with the capacity of herpesviruses, including bovine herpes virus 1 (BHV-1), to inhibit a number of the steps involved in processing and presentation of antigen to CD8 T cells [3, 4], reducing the efficiency of the CD8 T-cell response. The IE and E proteins are involved in regulating expression of other viral genes or modulation of host cell function, whereas products encoded by the L genes are generally structural components of the virion. Knowledge of which categories of viral protein are recognized by the CD8 T-cell response and the ability of the specific CD8 T cells to recognize virus-infected cells can inform the choice of antigens for inclusion in new vaccines
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