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Abstract
When Isaacs and Lindenmann discovered interferon in 1957, they described it as a compound possessing antiviral activities (Isaacs and Lindenmann, 1957). Since then, interferon has been implicated in many other biological processes, including cellular growth (Bradley and Met- calf, 1966) and differentiation (Ichihawa et al, 1966), immunological regulation (DeMaeyer and DeMaeyer-Guignard, 1977) and anti-tumor activities (Gresser, 1977). Despite these "other" activities of interferon, its role as a potent antiviral agent is one that remains an inportant research topic.
It has been well documented that different classes of viruses possess different relative sensitivities to interferon (Stephan et al, 1977), and that occasionally this difference is exhibited between vi- ruses in the same class (Oxman, 1973), or even in different strains of the same virus (Lomniczi, 1973), although the reason(s) for these differences remain unknown. It has been proposed (Fleischmann and Simon, 1973) that Mengovirus, a member of the picornavirus family, is able to produce a product directed against interferon, thereby blocking the induction of the antiviral state. It is not known whether this product was supposed to act in a manner analogous to a previously identified inhibitor of interferon production, the "blocker" (Isaacs et al, 1966). Quite apparent, however, was the need to investigate any possibility that viruses have the ability to produce substances which block inter- feron's action, especially as the use of interferon becomes more and nore widespread in clinical trials.
Simon (Purdue University) reasoned that if there was an active mechanism involved in confering interferon resistance to viruses, he could elucidate the factor(s) a virus might synthesize to overcome the interferon by generating and studying interferon-sensitive mutants. Si non mutagenized wildtype Nengovirus stocks with nitrous acid (Sinon et al, 1976) and selected for interferon-sensitive mutants via plaque formation in the presence or absence of one unit of interferon. After this one-step screening procedure, Sinon selected the 5 most sensitive mutants and determined the most sensitive (compared to wildtype) according to two criteria: 1) plaque reduction 50 (PR50) values and 2) yield reduction curves. By the first criterion, the most interferon-sensitive mutant isolated, is-1, was 1.5-2 times more sensitive to interferon than wild- type Mengovirus (is+). According to the second criterion, is-1 was 5- 10 times more sensitive to interferon than wildtype virus. To determine why is-1 showed enhanced sensitivity to interferon, Simon did coinfection experiments in which monolayers either untreated or treated with 2.5 units of interferon were infected with is only, is-1 only, or is and is-1 together (m-10). Simon reported that total virus yields from is infected cells either untreated or interferon pretreated were similar while is:1 yields in interferon pretreated cells were reduced by 90% compared to yields in untreated (control) cells, a result consis tent with, but not proof of, an interferon-sensitive phenotype. Coin- fection with is and is-1 in cells pretreated with interferon resulted in total yields of virus which nearly equalled yields from untreated cells. Since coinfection of interferon pretreated cells did not result in a significant reduction in total virus yield, Sinon concluded that is was dominant to is-1. A possible explanation proposed for the is dominance was that is-1 was deficient in a diffusible product which could be supplied by is in order to overcome the inherent interferon- sensitivity of is-1. However, Simon discounted this possibility by showing that the result of infection of interferon-protected L cells with is-1 was not identical to is infection of L cells protected with a higher level of interferon, as would be predicted.