Bovine Herpesvirus Type 1 (BHV-1) UL49.5 Luminal Domain Residues 30 to 32 Are Critical for MHC-I Down-Regulation in Virus-Infected Cells

Herman Favoreel,Huiyong Wei,Shafiqul I. Chowdhury,Ying Wang

doi:10.1371/journal.pone.0025742

Herman Favoreel, Huiyong Wei + Show 2 more

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https://doi.org/10.1371/journal.pone.0025742

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Journal: PLoS ONE	Publication Date: Oct 26, 2011
Citations: 34	License type: CC BY 4.0

Affiliation: Louisiana State University

Abstract

Bovine herpesvirus type 1 (BHV-1) UL49.5 inhibits transporter associated with antigen processing (TAP) and down-regulates cell-surface expression of major histocompatibility complex (MHC) class I molecules to promote immune evasion. We have constructed a BHV-1 UL49.5 cytoplasmic tail (CT) null and several UL49.5 luminal domain mutants in the backbone of wild-type BHV-1 or BHV-1 UL49.5 CT- null viruses and determined their relative TAP mediated peptide transport inhibition and MHC-1 down-regulation properties compared with BHV-1 wt. Based on our results, the UL49.5 luminal domain residues 30–32 and UL49.5 CT residues, together, promote efficient TAP inhibition and MHC-I down-regulation functions. In vitro, BHV-1 UL49.5 Δ30–32 CT-null virus growth property was similar to that of BHV-1 wt and like the wt UL49.5, the mutant UL49.5 was incorporated in the virion envelope and it formed a complex with gM in the infected cells.

Highlights

Bovine herpesvirus-1 (BHV-1) is an important cattle pathogen responsible for a wide variety of clinical diseases, including conjunctivitis and upper respiratory tract infection known as infectious bovine rhinotracheitis (IBR), reproductive tract lesions and abortion in pregnant cows, and systemic infection in the newborn [1,2,3]
Results of immunoprecipitation using UL49.5- or gM-specific rabbit polyclonal antibodies showed that i) amounts of wt and mutant UL49.5 cytoplasmic tail (CT)-null, UL49.5D30–32 CT-null, UL49.5D43–46 CT-null, and UL49.5D37–40 CT-null) immunoprecipitated by anti UL49.5 antibody in each case were very similar (Fig. 3), ii) the amount and molecular mass of mature gM coimmunoprecipitated by the anti UL49.5 antibody from infected cell lysates of BHV-1 wt, BHV-1 UL49.5 CT-null, BHV-1 UL49.5D30–32 CTnull, and BHV-1 UL49.5D43–46 CT-null viruses were very similar but in the case of BHV-1 UL49.5D37–40 CT-null, the amount of processed gM coimmunoprecipitated was reduced (Fig. 3), and iii) consistent with the latter results, with the exception of BHV-1 UL49.5D37–40 CT-null, anti gM antibody coimmunoprecipitated similar amounts of UL49.5 from the all the virus-infected cell lysates
Previous studies reported that following BHV-1 infection, transporter associated with antigen processing (TAP) function was inhibited and as a consequence major histocompatibility complex (MHC)-I surface expression was down-regulated [10,11]

Summary

Introduction

Bovine herpesvirus-1 (BHV-1) is an important cattle pathogen responsible for a wide variety of clinical diseases, including conjunctivitis and upper respiratory tract infection known as infectious bovine rhinotracheitis (IBR), reproductive tract lesions and abortion in pregnant cows, and systemic infection in the newborn [1,2,3]. The TAP1/TAP2 heterodimer undergoes conformational changes [5,6,7]. In BHV-1-infected cells, UL49.5 (BHV-1 homolog of envelope glycoprotein gN) binds to TAP, interferes with its peptide transport function and degrades the TAP [10,11]. BHV-1 interferes with the MHC class I antigen presentation pathway and during the initial phase of viral infection, escapes host cellular immune surveillance and elimination [11,12,13,14,15]. Problems associated with BHV-1 infection in the vaccinated animals exist, especially in the feedlot. Since both the traditional and gE-deleted MLVs have wildtype UL49.5, these vaccines like the wild-type virus, are transiently immunosuppressive. There is a need for further improvement of the current MLVs [16,17,18,19]

Methods

Results

Conclusion