title: Novel mutations in Marburg virus glycoprotein associated with viral evasion from antibody mediated immune pressure.
abstract: Marburg virus (MARV) and Ebola virus, members of the family Filoviridae, cause lethal haemorrhagic fever in humans and non-human primates. Although the outbreaks are concentrated mainly in Central Africa, these viruses are potential agents of imported infectious diseases and bioterrorism in non-African countries. Recent studies demonstrated that non-human primates passively immunized with virus-specific antibodies were successfully protected against fatal filovirus infection, highlighting the important role of antibodies in protective immunity for this disease. However, the mechanisms underlying potential evasion from antibody mediated immune pressure are not well understood. To analyse possible mutations involved in immune evasion in the MARV envelope glycoprotein (GP) which is the major target of protective antibodies, we selected escape mutants of recombinant vesicular stomatitis virus (rVSV) expressing MARV GP (rVSVΔG/MARVGP) by using two GP-specific mAbs, AGP127-8 and MGP72-17, which have been previously shown to inhibit MARV budding. Interestingly, several rVSVΔG/MARVGP variants escaping from the mAb pressure-acquired amino acid substitutions in the furin-cleavage site rather than in the mAb-specific epitopes, suggesting that these epitopes are recessed, not exposed on the uncleaved GP molecule, and therefore inaccessible to the mAbs. More surprisingly, some variants escaping mAb MGP72-17 lacked a large proportion of the mucin-like region of GP, indicating that these mutants efficiently escaped the selective pressure by deleting the mucin-like region including the mAb-specific epitope. Our data demonstrate that MARV GP possesses the potential to evade antibody mediated immune pressure due to extraordinary structural flexibility and variability.
authors.affiliation: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kajihara
authors.affiliation: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Nakayama
authors.affiliation: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Marzi
authors.affiliation: Division of Bioinformatics, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA.
authors.forename: Heinz
authors.initials: H
authors.lastname: Feldmann
authors.affiliation: School of Veterinary Medicine, the University of Zambia, P. O. Box 32379, Lusaka, Zambia.|Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020, Japan.
authors.forename: Ayato
authors.initials: A
authors.lastname: Takada
mesh_terms: D000350:Africa, Central; D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D029043:Ebolavirus; D016563:Filoviridae; D045683:Furin / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D006868:Hydrolysis; D057131:Immune Evasion; D029024:Marburgvirus / Q000235:genetics / Q000276:immunology*; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology; D009154:Mutation; D011323:Primates; D017384:Sequence Deletion; D018116:Vesiculovirus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; C081324:GP-protein, Marburg virus; D050505:Mutant Proteins; D014759:Viral Envelope Proteins; D045683:Furin