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Antigenic determinants of measles virus hemagglutinin associated with neurovirulence
U G Liebert1, S G Flanagan, S Löffler
1Institut für Virologie und Immunobiologie, Universität Würzburg, Germany.
Abstract:
The biological activity of monoclonal antibodies specific for the hemagglutinin protein of measles virus strain CAM recognizing six epitope groups according to their binding properties to measles virus strain CAM/R401 was investigated in vivo in our rat model of measles encephalitis. When injected intraperitoneally into measles virus-infected suckling rats, some monoclonal antibodies modified the disease process and prevented the necrotizing encephalopathy seen in untreated animals. The analysis of measles virus brain isolates revealed emergence of variants that resisted neutralization with the passively transferred selecting monoclonal antibody but not with other monoclonal antibodies. Monoclonal antibody escape mutants were also isolated in vitro, and their neurovirulence varied in the animal model. Sequence data from the hemagglutinin gene of measles virus localize a major antigenic surface determinant of the hemagglutinin protein between amino acid residues 368 and 396, which may be functionally important for neurovirulence. The data indicate that the interaction of antibodies with the measles virus H protein plays an important role in the selection of neurovirulent variants. These variants have biological properties different from those of the parent CAM virus.
Insights
Monoclonal antibodies targeting measles virus hemagglutinin can prevent encephalitis in rats. However, the virus can evolve escape mutants with altered neurovirulence, highlighting antibody-driven selection of viral variants.
Area of Science:
- Virology
- Immunology
- Neuroscience
Background:
- Measles virus causes encephalitis, a severe neurological complication.
- Monoclonal antibodies (mAbs) targeting viral proteins are potential therapeutics.
- The measles virus hemagglutinin (H) protein is crucial for viral entry and a key target for neutralizing antibodies.
Purpose of the Study:
- To investigate the in vivo biological activity of mAbs against measles virus hemagglutinin.
- To determine if mAbs can prevent measles virus-induced encephalitis in a rat model.
- To analyze the emergence and characteristics of measles virus variants selected by mAbs.
Main Methods:
- In vivo studies using a rat model of measles encephalitis.
- Intraperitoneal injection of measles virus-infected suckling rats with specific monoclonal antibodies.
- Isolation and characterization of measles virus brain and in vitro escape mutants.
- Sequence analysis of the measles virus hemagglutinin gene.
Main Results:
- Some mAbs administered intraperitoneally altered the disease course and prevented necrotizing encephalopathy in infected rats.
- Measles virus brain isolates exhibited resistance to neutralization by the selecting mAb, but not by others.
- Monoclonal antibody escape mutants were isolated in vitro, displaying varied neurovirulence in the animal model.
- A major antigenic surface determinant on the H protein was localized between amino acid residues 368 and 396.
Conclusions:
- Antibody interaction with the measles virus H protein significantly influences the selection of neurovirulent variants.
- These antibody-selected variants possess distinct biological properties compared to the parent virus.
- Understanding these interactions is critical for developing effective measles virus therapies and vaccines.