Unmasking the masters of evasion : TAP inhibition by varicellovirus UL49.5 proteins

The life-long infection by varicelloviruses is characterized by a fine balance between the host immune response and immune evasion strategies employed by these viruses. Virus-derived peptides are presented to cytotoxic T-lymphocytes by MHC I molecules. The transporter associated with antigen processing (TAP) transports the peptides from the cytosol into the endoplasmic reticulum, where the loading of MHC I molecules occurs. The UL49.5 protein of the varicelloviruse bovine herpesvirus 1 (BHV-1) is a potent inhibitor of TAP-mediated peptide transport. The viral protein prevents MHC I maturation by rendering the TAP complex in a translocation incompetent state. In addition, TAP proteins are degraded in the presence of BHV-1 UL49.5. The chapters 2 to 4 of this thesis focus on the functional dissection of BoHV-1 UL49.5 and aim to identify its target domain within the TAP complex. All herpesviruses sequenced to date code for a UL49.5 homolog. However, in chapter 5 and 6 we show that only a few viruses belonging to the genus Varicellovirus encode a TAP-inhibiting UL49.5. The applicability of the UL49.5 proteins to study and modify pathways of antigen presentation is demonstrated in chapter 7 and 8. Chapter 9 describes the identification of a TAP inhibitor in cowpox virusUBL - phd migration 201