Viral Inhibition of the Transporter Associated with Antigen Processing (TAP): A Striking Example of Functional Convergent Evolution

Abstract

Herpesviruses are large DNA viruses that are highly abundant within their host populations. Even in the presence of a healthy immune system, these viruses manage to cause lifelong infections. This persistence is partially mediated by the virus entering latency, a phase of infection characterized by limited viral protein expression. Moreover, herpesviruses have devoted a significant part of their coding capacity to immune evasion strategies. It is believed that the close coexistence of herpesviruses and their hosts has resulted in the evolution of viral proteins that specifically attack multiple arms of the host immune system. Cytotoxic T lymphocytes (CTLs) play an important role in antiviral immunity. CTLs recognize their target through viral peptides presented in the context of MHC molecules at the cell surface. Every herpesvirus studied to date encodes multiple immune evasion molecules that effectively interfere with specific steps of the MHC class I antigen presentation pathway. The transporter associated with antigen processing (TAP) plays a key role in the loading of viral peptides onto MHC class I molecules. This is reflected by the numerous ways herpesviruses have developed to block TAP function. In this review, we describe the characteristics and mechanisms of action of all known virus-encoded TAP inhibitors. Orthologs of these proteins encoded by related viruses are identified, and the conservation of TAP inhibition is discussed. A phylogenetic analysis of members of the family Herpesviridae is included to study the origin of these molecules. In addition, we discuss the characteristics of the first TAP inhibitor identified outside the herpesvirus family, namely, in cowpox virus. The strategies of TAP inhibition employed by viruses are very distinct and are likely to have been acquired independently during evolution. These findings and the recent discovery of a non-herpesvirus TAP inhibitor represent a striking example of functional convergent evolution.

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

“…4). Only a minority of all CD8 + T-cell epitopes (including those of viral origin) are expected to be TAPindependent (42), and the importance of TAP is reflected by the many herpesviruses that have evolved their own TAP-inhibitory proteins (54,55). A broad impact of TAP regulation on the immunological status in latency is also suggested by our observation that viral miRNAs do not affect global levels of HLA-A2, which is capable of presenting highly hydrophobic peptides that are more likely to be TAP-independent (39,56), but do reduce levels of the HLA class I allotypes tested (HLA-B7, B8, and B40).…”

Identification of immediate early gene products of bovine herpes virus 1 (BHV-1) as dominant antigens recognized by CD8 T cells in immune cattle

“…There is compelling evidence that they are required to prevent reactivation of latent infection and that they also contribute to resolution of the acute phase of infection [1,2]. The prominent role of CD8 T cells in immunity is also 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], thus reducing the efficiency of the CD8 T-cell response.…”

Structure determination of UL49.5 transmembrane protein from bovine herpesvirus 1 by NMR spectroscopy and molecular dynamics

“…Recently, the 3D structure of TAP bound to herpes simplex virus 1-encoded ICP47 protein was obtained using electron cryomicroscopy [12]. To the best of our knowledge, there is no information regarding the molecular structure of TAP in a complex with other viral transmembrane proteins, such as the US6 protein of human cytomegalovirus, the BNLF2a protein of the Epstein-Barr virus, the CPXV012 protein of the cowpox virus (reviewed in [13]), or any of the varicella virus-encoded UL49.5 [13].…”