Monoclonal Antibodies Which Recognize the Acidic Configuration of the Rabies Glycoprotein at the Surface of the Virion Can Be Neutralizing

Around 15% of our anti-glycoprotein monoclonal antibodies (MAbs) failed to neutralize the infectivity of the rabies virus during a 1-hr incubation at room temperature. In previous studies, we have demonstrated that it is possible to induce a massive conformational change of the glycoprotein populati...

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Veröffentlicht in:Virology (New York, N.Y.) N.Y.), 1995-07, Vol.210 (2), p.400-408
Hauptverfasser: Raux, Hélène, Coulon, Patrice, Lafay, Florence, Flamand, Anne
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Flamand, Anne
description Around 15% of our anti-glycoprotein monoclonal antibodies (MAbs) failed to neutralize the infectivity of the rabies virus during a 1-hr incubation at room temperature. In previous studies, we have demonstrated that it is possible to induce a massive conformational change of the glycoprotein population by incubating the virus at acidic pH. The conformational change is reversible and consequently viral infectivity is not affected by transient exposure at acidic pH. The proportion of glycoproteins in acidic or neutral configuration depends on the pH which means that even at neutral pH some glycoproteins transiently adopt the acidic configuration and vice versa. Here we report that some of our nonneutralizing MAbs recognize the acidic form of the glycoprotein at the virion surface. After incubation of the virus at pH 64, most glycoproteins are in the acidic configuration. Further 1-hr incubation with these MAbs at the same pH resulted in more immunoglobulins being attached to the virus and consequently neutralization was induced. It was also possible to induce neutralization with the same MAbs by incubation at neutral pH for a longer period or at a higher temperature. Mutants resistant to neutralization by these MAbs could be selected. Mutations confering resistance to neutralization were not localized in previously described antigenic sites and did not modify these sites at distance. They had no effect on the pathogenic power of the virus. Either they are situated in the epitope or they modify the epitope, so that it is no longer recognized by the antibody on the acidic configuration of the protein. Alternatively, these mutations may stabilize the protein in its neutral configuration. In addition, these experiments confirm our previous finding that neutralization requires the fixation of a large number of immunoglobulins on the virus, irrespective of the region of the protein recognized by the antibody.
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In previous studies, we have demonstrated that it is possible to induce a massive conformational change of the glycoprotein population by incubating the virus at acidic pH. The conformational change is reversible and consequently viral infectivity is not affected by transient exposure at acidic pH. The proportion of glycoproteins in acidic or neutral configuration depends on the pH which means that even at neutral pH some glycoproteins transiently adopt the acidic configuration and vice versa. Here we report that some of our nonneutralizing MAbs recognize the acidic form of the glycoprotein at the virion surface. After incubation of the virus at pH 64, most glycoproteins are in the acidic configuration. Further 1-hr incubation with these MAbs at the same pH resulted in more immunoglobulins being attached to the virus and consequently neutralization was induced. 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subjects Amino Acid Sequence
Animals
Antibodies, Monoclonal - immunology
Antibodies, Viral - immunology
Antibody Specificity
Antigens, Viral
DNA Mutational Analysis
Epitopes - chemistry
Epitopes - immunology
Female
Glycoproteins - chemistry
Glycoproteins - genetics
Glycoproteins - immunology
Hydrogen-Ion Concentration
Mice
Molecular Sequence Data
Mutation - physiology
Neutralization Tests
Protein Conformation
rabies virus
Rabies virus - immunology
Rabies virus - pathogenicity
Viral Envelope Proteins - chemistry
Viral Envelope Proteins - genetics
Viral Envelope Proteins - immunology
Virion - immunology
title Monoclonal Antibodies Which Recognize the Acidic Configuration of the Rabies Glycoprotein at the Surface of the Virion Can Be Neutralizing
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