The herpesvirus stealth program

Immune evasion represents a critical strategy that many viruses have evolved to ensure survival in individual hosts and entire populations. In vertebrates, particularly mammals that are protected by a highly sophisticated immune system, viruses need to antagonize the many defense line drawn after antigen recognition and the ensuing differentiation and proliferation of virus-specific T and B cells. The Herpesviridae family is characterized by complex viral genomes that contain a number of so-called non-essential genes, which are dispensable for growth in cultured cells but not in vivo. It is no surprise that herpesviruses encode, among many other immune evasion factors, gene products that target antigen presentation by major histocompatibility complex class I (MHC-I) [1]. Due to the drastic reduction of cell surface MHC-I molecules, the signals that activate and recruit cytotoxic T lymphocytes (CTLs) to the infected cell are blocked. As a result, the infected cells cannot be eliminated and thus become a reservoir for the sustained production and release of viruses. The viral inhibitors that cause downregulation of MHC-I on the cell surface can vary widely with respect to mechanistic principles, even among closely related virus species. For instance, some pUL49.5 homologues from the Varicellovirus genus of the Alphaherpesviridae have been shown to interfere with the MHC-I presentation pathway. The viral proteins block the physiological activity of the transporter associated with antigen processing (TAP) that facilitates translocation of peptides produced by the proteasome into the endoplasmic reticulum (ER) and ultimately loading of antigenic peptides onto MHC-I. Regardless of the structural similarities, there are remarkable differences in the molecular functions exerted by pUL49.5 homologues. In the case of bovine herpesvirus 1 (BoHV-1), the TAP complex is tagged for proteasomal degradation by pUL49.5, whereas the pUL49.5 homologues of equine herpesvirus 1 (EHV1) and EHV-4 impair the function of the TAP complex merely through inhibition of ATP binding (reviewed in [2]). Apart from the pUL49.5 homologues, the EHV-1 pUL56 was shown to be involved in downregulation of cell surface MHC-I [3]. Detailed studies revealed that early in infection the expression of pUL56 correlates with internalization of cell surface MHC-I through dynamindependent endocytosis, a process that requires activation of the cellular ubiquitination cascade [4]. Knowing that pUL56 suppresses the MHC-I presentation only during viral infection and not by itself, we speculated that there is at least one viral interactor of pUL56. We, therefore, Editorial