Structural and Nonstructural Viral Proteins Are Targets of T-Helper Immune Response against Human Respiratory Syncytial Virus

Elena Lorente,Alejandro Barriga,Eilon Barnea,Carmen Mir,John A Gebe,Arie Admon,Daniel López

doi:10.1074/mcp.m115.057356

Abstract

Proper antiviral humoral and cellular immune responses require previous recognition of viral antigenic peptides that are bound to HLA class II molecules, which are exposed on the surface of antigen-presenting cells. The helper immune response is critical for the control and the clearance of human respiratory syncytial virus (HRSV) infection, a virus with severe health risk in infected pediatric, immunocompromised, and elderly populations. In this study, using a mass spectrometry analysis of complex HLA class II-bound peptide pools that were isolated from large amounts of HRSV-infected cells, 19 naturally processed HLA-DR ligands, most of them included in a complex nested set of peptides, were identified. Both the immunoprevalence and the immunodominance of the HLA class II response to HRSV were focused on one nonstructural (NS1) and two structural (matrix and mainly fusion) proteins of the infective virus. These findings have clear implications for analysis of the helper immune response as well as for antiviral vaccine design.

Highlights

Synthesized HLA class II molecules from antigenpresenting cells associate with the class II invariant chain (Ii)
Three major issues could be derived from the results reported here about the nature and hierarchy of the T cell class-II-specific response against Human respiratory syncytial virus (HRSV)
It is commonly assumed that the MHC class II ligands are generated in a first step by proteolytic activity of lysosomal proteases on the protein antigens and later the resulting peptides bind to MHC class II molecules, this “cut/ trim first, bind later” model is inherently problematic because proteolytic fragments are rare and short lived in the terminal degradative lysosome environment

Summary

Introduction

Synthesized HLA class II molecules from antigenpresenting cells associate with the class II invariant chain (Ii). We are interested in the identification of viral ligands that are presented by several frequent HLA-DR class II molecules in HRSV-infected cells to analyze how the immune system selects natural HLA class II ligands and epitopes.

Results

Conclusion