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Title: The interaction of influenza virus with neutralizing antibody
Author: Taylor, Howard Paul
ISNI:       0000 0001 3505 0823
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 1986
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The polymeric antibodies secretory IgA (slgA) and IgM are important in immunity to influenza virus and this work was undertaken primarily to investigate the mechanisms by which they neutralized type A influenza virus (A/fowl plague virus/Rostock/34; H7N1) (FPV/R). Secondly, this thesis presents data on the quantitative aspects of neutralization by monoclonal and polyclonal IgG, focusing particularly on the number of antibody molecules binding to virus particles at minimum and maximum levels of neutralization. The attachment of FFV/R neutralized by slgA and IgM was completely blocked at 4°C. The large molecular structure of these antibodies suggests that steric hindrance may be the mechanism by which attachment is impaired. However at 25 and 37°C neutralizing slgA and IgM inhibited attachment of only 50% of the neutralized virus and none of this attached virus was internalized. It is inferred that IgM and slgA interfere with the endocytotic event responsible for internalization of virus. In contrast when neutralized by either IgG or monomeric IgA (obtained from the partial reduction of the above slgA), FPV/R attached to and penetrated into BHK-21 cells, with the genome accumulating in the nucleus, at a rate indistinguishable from that of non-neutralized virus. This behaviour was independent of temperature from 4 to 37°C. Thus IgG and monomeric IgA neutralized infectivity at a stage subsequent to penetration. Virus was neutralized by F(ab')2 and Fab’ fragments of monoclonal anti-HA IgG. Neither prevented the attachment, penetration, or the accumulation of viral genomes in the nucleus. Radiochemical data obtained on the binding of immunoglobulins (IgG, slgA) to the haemagglutinin (HA) of FFV/R in suspension suggests that the virus is saturated at approximately one four-chain immunoglobulin unit per HA spike. Two-step competition assays show that the binding of one molecule of monoclonal IgG to a HA spike prevents the binding of monoclonal antibodies to two different epitopes on that spike and also the binding of polyclonal antibody to the HA. These observations argue against direct epitope-epitope competition and for a steric or allosteric block on the binding of further IgG to the HA spike by prebound IgG. The kinetics of neutralization of FPV/R at 4°C with minimal concentrations of monoclonal IgG suggested that 3 IgG molecules were required to neutralize an infectious virus particle. The discrepancy between this and radiochemical data indicating that least 50 antibodies per virus particle are required for neutralization i3 reconciled by a theory that neutralization only occurs when antibody binds to certain "neutralization relevant" HA spikes, which are in the minority, and differ from "neutralization irrelevant" spikes only in their interaction with the viral core.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR180 Immunology