Bovine Herpesvirus 1 UL49.5 Protein Inhibits the Transporter Associated with Antigen Processing despite Complex Formation with Glycoprotein M

Abstract

Bovine herpesvirus 1 (BHV-1) interferes with peptide translocation by the transporter associated with antigen processing (TAP). Recently, the UL49.5 gene product of BHV-1 was identified as the protein responsible for the observed inhibition of TAP. In BHV-1-infected cells and virions, the UL49.5 protein forms a complex with glycoprotein M (gM). Hence, it was investigated whether UL49.5 can combine the interactions with gM and the TAP complex. In cell lines constitutively expressing both UL49.5 and gM, UL49.5 appears to be required for functional processing of gM. Immunofluorescence-confocal laser scanning microscopy demonstrated that both proteins are interdependent for their redistribution from the endoplasmic reticulum to the trans-Golgi network. Remarkably, expression of cloned gM results in the abrogation of the UL49.5-mediated inhibition of TAP and prevents the degradation of the transporter. However, in BHV-1-infected cells, differences in UL49.5 and gM expression kinetics were seen to create a window of opportunity at the early stages of infection, during which time the UL49.5 protein can act on TAP without gM interference. Moreover, in later periods, non-gM-associated UL49.5 can be detected in addition to the UL49.5/gM complex. Thus, it has been deduced that different functions of UL49.5, editing of gM processing and inhibition of TAP, can be combined during BHV-1 infection.

Bovine herpesvirus 1 infection and infectious bovine rhinotracheitis

“…Nevertheless, it has a conserved function and forms a disulfide-linked heteroduplex together with gM [115,224]. All BoHV-1 genes are classified into two main categories based on the impact of deletion of a single gene on the ability of mutant virus to grow in cell culture.…”

“…In order to diminish the detection and the elimination of virus-infected cells by cytotoxic T lymphocytes, BoHV-1 was shown to down-regulate antigen presentation by the class I major histocompatibility complex (MHC class I) [95,96,115,146]. Two independent mechanisms are responsible for down-regulation of MHC class I molecules.…”

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

“…48), anti-GFP (49), anti-huTAP1 mAb 148.3 (50,51), anti-huTAP2 mAb 435.3 (52) (provided by P. van Endert, Faculté de Médecine René Descartes, Paris, France), goat anti-rat TAP1 M18 (Santa Cruz Biotechnology; used for Western blotting), rabbit anti-rat TAP1 D90 (53) (used for immunoprecipitation), anti-rat TAP2 mAb Mac394 (54) (used for Western blotting), sheep anti-rat TAP2 S635 (provided by S. Powis, Bute Medical School,(Serotec), anti-MHC class II L243-PE (BD Pharmingen), and anti-NGFRbiotin (BD Pharmingen) were used. For detection of UL49.5, a rabbit polyclonal anti-serum (H11) was raised using a synthetic peptide derived from the N-terminal domain of BHV-1 UL49.5 as an Ag (56). mAbs against human transferrin receptor (CD71; BD Biosciences) and human transferrin receptor (H68.4; Roche Diagnostics) were used as controls.…”

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

“…BHV-1 infects cells of the respiratory and reproductive tracts and causes clinical diseases, namely infectious bovine rhino-tracheitis and infectious pustular vulvo-vaginitis [14], which result in significant production losses in affected herds, including the death of some animals. BHV-1-encoding proteins have a number of immunomodulatory activities, including downregulation of type I interferon responses [15] and expression of class I MHC proteins [16], and interference with chemokine activities [17], which collectively are associated with suppressed cellular immune responses during infection. This immunosuppression is implicated in predisposition to secondary infections with other respiratory pathogens, both viral and bacterial, which cause severe disease and mortality in intensive cattle-rearing units (reviewed in [18]).…”