Mutations in the H, F, or M Proteins Can Facilitate Resistance of Measles Virus to Neutralizing Human Anti-MV Sera

Els Verhoeyen,François-Loïc Cosset,Robin Buckland,Hasan Kweder,Camille Lévy,Claude P Muller,Sara Louise Cosby,Michelle Ainouze,Evelyne Manet

doi:10.1155/2014/205617

Els Verhoeyen, François-Loïc Cosset + Show 7 more

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https://doi.org/10.1155/2014/205617

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Abstract

Although there is currently no evidence of emerging strains of measles virus (MV) that can resist neutralization by the anti-MV antibodies present in vaccinees, certain mutations in circulating wt MV strains appear to reduce the efficacy of these antibodies. Moreover, it has been hypothesized that resistance to neutralization by such antibodies could allow MV to persist. In this study, we use a novel in vitro system to determine the molecular basis of MV's resistance to neutralization. We find that both wild-type and laboratory strain MV variants that escape neutralization by anti-MV polyclonal sera possess multiple mutations in their H, F, and M proteins. Cytometric analysis of cells expressing viral escape mutants possessing minimal mutations and their plasmid-expressed H, F, and M proteins indicates that immune resistance is due to particular mutations that can occur in any of these three proteins that affect at distance, rather than directly, the native conformation of the MV-H globular head and hence its epitopes. A high percentage of the escape mutants contain mutations found in cases of Subacute Sclerosing Panencephalitis (SSPE) and our results could potentially shed light on the pathogenesis of this rare fatal disease.

Highlights

Measles virus is (MV), a member of the genus Morbillivirus in the family Paramyxoviridae
The H protein is responsible for attachment to the cellular receptors of MV and the F protein is responsible for the consequent fusion of the virion membrane with the host cell’s plasma membrane whereby the ribonucleoprotein complex (RNP) is delivered into the cytoplasm, and the matrix protein M lines the inner surface of the virion membrane [1]
As the MV-H glycoprotein appears to be the principal target for these antiMV sera [9], we introduced mutations into the major epitopes of the MV-H globular head to try to overcome this problem [10]

Summary

Introduction

Measles virus is (MV), a member of the genus Morbillivirus in the family Paramyxoviridae. The glycoproteins accumulate in the plasma membrane This allows the H protein to interact with cellular receptors on neighboring uninfected cells and cause cell-cell fusion (syncytia formation) through activation of the F protein. In the case of the infected cell, evidence exists to suggest that the M protein interacts with the cytoplasmic tails of the glycoproteins H and F at the plasma membrane [2, 3]. To determine the effect of these mutations separately, mutations were introduced separately in the different genes using the QuickChange mutagenesis kit (Stratagene) according to the manufacturer’s instructions. These mutations were introduced in the genes encoding the H, F, and M proteins cloned into the plasmid phCMV.

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