Mutation and selection pressure during adaptation of influenza virus to mice

Egg-line strains of type A′ and type B influenza viruses which are sensitive to the hemagglutinin-inhibiting and neutralizing activity of β-inhibitor may produce mutants which are resistant to β-inhibitor. These resistant mutants may be selected in ovo by introducing β-inhibitor in the form of bovine serum into the allantoic cavity. Resistant virus thus isolated has a more rapid growth rate and an enhanced survival advantage in mouse lungs and is pathogenic on initial inoculation into mice. By the method and equation of Luria and Delbrück (Luria and Delbrück, 1943; Newcombe, 1948), the mutation rate from sensitivity to resistance to β-inhibitor has been calculated to be between 3.3 × 10 −8 and 7.0 × 10 −9 for different strains of influenza virus. During the adaptation of sensitive virus to mice, mixed populations of sensitive and resistant particles can be detected immediately prior to the appearance of extensive pulmonary consolidation. The proportion of resistant particles in the population rapidly increases until the majority are resistant, at which time the virus is adapted. Resistant virus does not appear to be enzymatically active against β-inhibitor.