238 F. FENNER AND J. CAIRNS 



earlier in the fowl cell gradient, had reduced enzymatic action against 

 ovomucin, and was less virulent to mice (Isaacs and Edney, 1950). 



This, then, is probably the most liberally documented instance of variation 

 in virulence of a virus being associated with changes in in vitro behavior. 

 There is, however, evidence that the association is not always perfect. 

 Variants with extreme insensitivity to inhibitors may be obtained by passage 

 of virus in eggs in the presence of bovine serum inhibitor; these variants, 

 which arise with a frequency of about 10 -8 (Medill-Brown and Briody, 1955) 

 are not, however, fully adapted to mice (Chu, 1951). Conversely, during the 

 process of adaptation to mice, clones of virus maybe isolated which apparently 

 are fully adapted to mouse lung and yet almost unaltered in their in vitro 

 properties (Ledinko, 1956). 



Unfortunately, there is more conflict of opinion over the nature of the 

 change in in vivo behavior during adaptation; indeed, the conclusion seems 

 inescapable that not all unadapted strains are unadapted for the same reason. 

 Much of this difficulty is due to the exceedingly complex behavior of un- 

 adapted virus on first introduction to the mouse lung. Inoculation of large 

 amounts of unadapted virus into mice results in extensive lung consolidation; 

 on subinoculation of a suspension of these consolidated lungs little or no lung 

 lesions result, and it is only after several more such passages — usually 

 unaccompanied by any lung lesions and therefore constituting "blind" 

 passages — that lung lesions reappear and become a regular feature of each 

 passage (Anderson and Burnet, 1947; Sugg, 1949). In general, it seems that 

 all unadapted strains are capable of multiplying in mouse lung at the first 

 passage (Burnet and Stone, 1945b; Hirst, 1947b; Wang, 1948; Sugg, 1950; 

 Davenport and Francis, 1951; Ginsberg, 1953a; Ledinko and Perry, 1955; 

 Ledinko, 1956). [There has been only one suggestion that lesions may be 

 produced in the absence of virus multiplication, and this example, the case of 

 the related virus, Newcastle disease virus, is open to very considerable 

 objection (Ginsberg, 1951)]. There is no doubt however that, in terms of 

 hemagglutinin titer or infectivity for the allantois, unadapted strains produce 

 lung consolidation and death much less readily than adapted strains. Part of 

 this difference is probably due to the fact that, in terms of capacity to initiate 

 multiplication, unadapted strains are about one hundred times less infective 

 for mouse lung than adapted strains (Ginsberg, 1953b). But most of the 

 difference in pathogenicity of unadapted and adapted strains almost 

 certainly depends on the difference in their behavior once multiplication has 

 been initiated. 



Studies on the relative multiplication rates and final yields of adapted and 

 unadapted strains in mouse (or hamster) lung have given conflicting results. 

 In some cases, there is a clear increase in the rate of multiplication with 

 adaptation (Wang, 1948; Ledinko, 1956), in some cases, not (Davenport and 



