Down-regulation of MHC class I expression by equine herpesvirus-1

Abstract

There is good evidence that cytotoxic T lymphocytes play an important role in the clearance of equine herpesvirus-1 (EHV1) in horses. We have demonstrated that, in common with other alphaherpesviruses, EHV1 infection can lead to dramatic down-regulation of MHC class I expression at the cell surface, a common strategy for pathogen evasion of the host immune response. This down-regulation is specific for MHC class I and does not reflect a general shut-off of host-cell protein synthesis. The use of monoclonal antibodies that recognize different MHC class I epitopes has demonstrated that the effect may be allele-or locus-specific. Use of the viral DNA synthesis inhibitor phosphonoacetic acid, which prevents late viral gene expression, showed that the effect is mediated by an immediate-early or early viral gene, and use of the protein translation inhibitor cycloheximide confirmed that an early gene is primarily responsible. The data indicate that EHV1 infection results in enhanced endocytosis of MHC class I from the cell surface; the only other herpesvirus reported to use this mechanism is human herpesvirus-8. Elucidation of the precise mechanisms used by EHV1 in this process and identification of the genes responsible may lead to improved vaccination strategies.

Down-regulation of MHC class I expression in human neuronal stem cells using viral stealth mechanism

“…This demonstrates that each hCMV US gene actually operated in the HB1.F3 cells although the down-regulation efficiencies of the introduced US genes differ from each other. The discrepancy of these US gene products to affect MHC class I expression might be due to the difference in their allele-specificity and/or their ability to down-regulate MHC class I expression [46][47][48]. In spite of their apparent down-regulation effects on the MHC class I expression in NSCs, it is uncertain whether the 25-50% reduction of MHC expression by transiently introduced hCMV US genes is satisfactory in escaping from T cell response.…”

“…The use of dominant negative regulators of MHC class I expression has some advantages over the complete elimination of MHC class I expression by targeting genes such as b 2 m and TAP (transporter associated with antigen processing). Leaving some MHC class I molecules but not their complete elimination by the dominant negative regulators might prevent the US gene-transfected cells from being immunocompromised and allow them to become resistant to cytotoxicity from the natural killer (NK) cells, which recognize cells lacking MHC class I expression [48,50].…”

Equus caballus Major Histocompatibility Complex Class I Is an Entry Receptor for Equine Herpesvirus Type 1

“…This immune evasion mechanism is mediated by the UL49.5 protein that is highly conserved within the Alphaherpesvirinae (11). In addition to interfering with TAP, EHV-1 has also been shown to decrease overall MHC-I expression on the cell surface at very early times postinfection (3,37,43,44). Rappocciolo et al concluded from their study that the downregulation of MHC-I is most likely mediated by an EHV-1 early gene.…”

Virus Evasion of MHC Class I Molecule Presentation

“…Separate motifs within the K3 protein are responsible for the endocytosis of MHC class I molecules and for targeting them for lysosomal degradation in a tumor susceptibility gene 101-dependent sorting process (37,38). A related virus that is a horse pathogen, equine herpesvirus-1, has likewise been shown to cause endocytosis of cell surface MHC class I molecules (58).…”