Infection and humoral immunity

Influenza in mammals, including humans, is essentially an aerosol infection confined to epithelial cells in the upper and lower respiratory tract. The disease in birds is different, being largely gastrointestinal in nature and spread by fecal contamination. Some of the avian viruses (H5 and H7) are so virulent that death may result from generalized infection with central nervous system involvement.

Mucosal (IgA) and serum (IgG) antibodies to the HA molecule neutralize virus infectivity and are primarily responsible for resistance to reinfection. This is the basis of vaccination against current epidemic strains with killed virus. The immunoglobulin (Ig) response to the HA is subtype specific, but accumulation of point mutations (antigenic drift) permits infectious virus to escape antibody-mediated destruction. Five antigenic sites, all of which are associated with protection, have been identified on the globular head of the HA molecule. 'Antigenic drift' results from the accumulation of amino acid substitutions at these sites, reproduced in the laboratory by selection of escape mutants with mouse monoclonal antibodies (mAbs). In addition, crystal-lographic studies with the mutants have shown that the antibodies bind to the regions of the molecule where the amino acid substitutions occur.

Antibodies to the neuraminidase do not prevent infection but reduce the spread of virus. The enzyme-

active centers on each of the four subunits of the NA lie in a central cavity surrounded by two antigenic sites. Escape mutants can again be selected with mAbs to these sites, which inhibit virus release by blocking enzyme activity. Complexes of NA-Fab have been crystallized and their structure established. Each defines an epitope comprising five polypeptide loops on the NA, involving about 22 amino acids in direct contact.

Variability is the key feature of the influenza A viruses. This depends on two, separate mechanisms. Antigenic drift (see above) gives rise to variants of existing epidemic strains which are sufficiently different from their predecessors to escape neutralization by the Ig pool available in the population at risk. The more profound change associated with 'antigenic shift' may result from a chance dual infection with a human and an animal influenza A virus. Re-assortment of the segmented genomes of the two viruses can then lead to the emergence of a novel pandemic strain, for which there is no pre-existing antibody in humans. Such reassortants are readily generated experimentally.

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