Neurovirulence of influenza A virus.

Infection of mouse brain with influenza A virus has provided a valuable model for investigating viral adaptation and virulence. These studies have indicated important roles for the neuraminidase (NA), matrix (M), non-structural (NS) and haemagglutinin (HA) genes of the virus in determining neurovirulence. For the NA, three changes close to the active site have been identified in the neurovirulent strains, which also display altered enzyme properties, including changes in specificity. In the M gene, two specific amino acid substitutions in the M1 protein have been observed, Ala41-->Val and Thr139-->Ala, which correlate with increased virulence for mouse. Such changes are likely to affect the pH-dependent association/dissociation of M1 with the viral ribonucleoprotein, as well as growth and virulence. The changes in the NS gene in the neurovirulent strains cause alterations in the mRNA secondary structure to mask the 3' splice site, and correlate with reduced splicing of the NS gene in these strains. Finally, the increased virulence of the HA gene occurs by at least three different mechanisms: loss of a glycosylation site, a change at the cleavage site, and a substitution which may increase the pH of fusion. These observations define a useful set of parameters with which to analyse epidemic virus strains that have been associated with elevated CNS symptoms in humans. In addition, the changes present in the neurovirulent influenza strains show interesting parallels to those in the neurovirulent derivatives of other viruses, suggesting different viruses utilise common strategies to permit replication in the brain.