Viral interference with antigen presentation: trapping TAP

Following primary infection, herpesviruses persist for life in their hosts, even when vigorous anti-viral immunity has been induced. Failure of the host immune system to eliminate infected cells is facilitated by highly effective immune evasion strategies acquired by these herpesviruses during millions of years of co-evolution with their hosts. Here, we review the mechanisms of action of viral gene products that lead to cytotoxic T cell evasion through interference with the function of the transporter associated with antigen processing, TAP. The viral TAP inhibitors impede transport of peptides from the cytosol into the ER lumen, thereby preventing peptide loading onto MHC class I complexes. Recent insights have revealed a pattern of functional convergent evolution. In every herpesvirus subfamily, inhibitors of TAP function have been identified that are, surprisingly, unrelated in genome location, structure, and mechanism of action. Recently, cowpox virus has also been found to encode a TAP inhibitor. Expanding our knowledge on how viruses perturb antigen presentation, in particular by targeting TAP, not only provides information on viral pathogenesis, but also reveals novel aspects of the cellular processes corrupted by these viruses, notably the translocation of peptides by the ATP-binding cassette (ABC) transporter TAP. As the various TAP inhibitors are anticipated to impede discrete conformational transitions it is expected that crystal structures of TAP-inhibitor complexes will reveal valuable structural information on the actual mechanism of peptide translocation by TAP. Viral TAP inhibitors are also used for various (clinical) applications, for example, as effective tools in antigen presentation studies and as immunomodulators in immunotherapy for cancer, heterologous vaccination, and transplant protection.