Evasion of MHC class I antigen presentation by cowpox virus

Orthopoxviruses are clinically important infectious agents. In their large DNA genomes, orthopoxviruses encode many immune evasion genes targeting both innate and adaptive immune effectors. Although previous studies suggested that CD8 T cells play an important role in defense against orthopoxvirus infection, evasion of CD8 T cell responses by orthopoxvirus has not been reported. This is in contrast with other DNA viruses that encode one or more genes inhibiting MHC class I antigen presentation to escape antiviral CD8 T cell responses.;Cowpox virus (CPXV), an orthopoxvirus with wild rodent reservoirs, is ideal for the study of orthopoxvirus-encoded immune evasion mechanism. We demonstrated that CPXV downregulates MHC class I molecules on the cell surface. Two CPXV-encoded proteins that mediate MHC class I downregulation, CPXV203 and CPXV12, were identified by gain-of-function and loss-of-function screening, respectively. Our data suggest that both proteins inhibit the trafficking of MHC class I molecules to the cell surface, but via distinct mechanisms. CPXV203 physically interacts with MHC class I molecules and retains them in the ER via its C-terminal KDEL-like motif, whereas CPXV12 impairs optimal peptide loading of MHC class I. Viruses deleted of both CPXV12 and CPXV203 were unable to downregulate MHC class I and exhibited attenuated virulence in murine hosts. CD8 T cells did not confer protection against CPXV if these proteins were expressed, indicating MHC class I downregulation can abrogate antiviral CD8 T cell response against CPXV.;Taken together, we report the original observation of CPXV-mediated MHC class I downregulation and demonstrate its molecular bases. Importantly, we provide in vivo evidence that CPXV escapes antiviral CD8 T cell response by evading MHC class I antigen presentation. Our study contributes to better understanding of the interaction between orthopoxviruses and their hosts.