166 R. W. SCHLESINGER 



challenge with a heterotypic strain, while homologous resistance lasted for 

 at least two years. It seems quite reasonable to suggest that early protection 

 against heterologous strains may have been due to interference rather than to 

 cross-reacting antibody. 



The distinction between specific immunity and interference as the basis for 

 host resistance was brought out sharply in studies on eastern and western 

 equine encephalomyelitis (EEE and WEE) viruses by Schlesinger et al. 

 (1943, 1944). Vaccination of rabbits, guinea pigs, or mice with formalin- 

 killed WEE virus induced long-lasting protection against intracerebral 

 challenge doses of the homologous, not the heterologous virus. Homologous 

 challenge led to transient infection whose abortion was associated with a 

 marked local, type-specific antibody response (Schlesinger et al., 1944; 

 Schlesinger, 1949). After such an abortive infection, the animals resisted 

 intracerebral superinfection with massive doses of the heterologous virus. 

 This type of resistance was effective for relatively short periods of time and was 

 not associated with anamnestic antibody response. It was therefore considered 

 as due to interference. 



Influenza has provided experience on a much larger scale than the examples 

 cited to show that "minor" cross-reacting antigens and antibodies do not 

 afford protection against variant strains, even of a single serotype. Evidence 

 is rapidly accumulating which points to the persistent association of viruses 

 with cells — both in tissue cultures and in the intact host. Indeed, presence of 

 protective antibody encourages rather than discourages lingering infection 

 (Ackermann and Kurtz, 1955). It seems reasonable to propose that such 

 conditions may set the stage for effective maintenance of interference as a 

 mechanism of cross protection. Apparently a curious paradox has arisen in 

 our thinking about this phenomenon: because the most penetrating studies on 

 interference have been done on simple model systems, viz., the allantoic 

 membrane and tissue cultures, we tend to shrug off the possibility that it may 

 be an inevitable and significant phase in the evolution of any, even the 

 natural, host-virus relationship. 



2. Homologous Viruses 



In general, the demonstration of homologous interference depends on a 

 difference in virulence between two variants of the same virus. The evaluation 

 of such systems is based either (a) on protection of the host (or of cells) 

 against the virulent variant or (b) on assay of the viral progeny for the 

 virulent component. Examples of this sort, other than those concerned with 

 influenza virus in eggs, are listed in Table II. The interfering agent in all 

 these cases is active virus. Since interfering and challenge virus are anti- 

 genically indistinguishable and genetically related, the distinction of inter- 

 ference from immunological phenomena and genetic interaction is much 

 more difficult than for heterologous pairs. 



