Interferon Induction by Viruses. VII. Mengovirus: "Interferon-Sensitive" Mutant Phenotype Attributed to Interferon-Inducing Particle Activity

Abstract

We hypothesize that the "interferon-sensitive" phenotype of a Mengovirus mutant, is-l, results from an interferon-inducing particle activity of the virion rather than an intrinsic sensitivity of the mutant virus to IFN action. Mutant is-l proved to be an excellent inducer of IFN, inducing over 25,000 units per 4 × 10⁶ mouse L(Y) cells. Its wildtype parent, is⁺, induced less than 5% as much IFN. We propose that the phenotype of the mutant virus is expressed when IFN induced by is-l particles in cells previously exposed to exogenous IFN feeds-back and acts on surrounding cells, and possibly on the self-same cells. We suggest that the resulting elevated levels of an interferon-mediated antiviral state in these cells make it appear that the mutant virus is more sensitive to IFN than its progenitor. The end effect, through the additional action of this endogenously induced interferon, is to reduce further the yield of infectious virus, and enhance cell-sparing—creating the phenotypic characteristics ascribed to mutant is-l. The abrogation of the is-l phenotype in the presence of wildtype (is⁺) virus or in cells treated with actinomycin D is accounted for by demonstrating that cells coinfected with is⁺ and is-l virus or treated with the drug fail to produce interferon. As proof of this hypothesis we demonstrate that both the "interferon-sensitive" mutant and its wildtype progenitor are equally sensitive to IFN action when tested on cells incapable of responding to inducers of IFN. Dose (multiplicity)-response (IFN yield) curves generated by infecting mouse L(Y) cells with this IFN-inducing mutant virus fit best a model in which all cells infected with only one infectious particle produce a quantum yield of IFN, whereas cells infected with 2 or more particles produce little or no interferon. Analyses of these curves provide quantitation of the IFN-inducing particle (IFP) activity of mutant is-l stocks, and in concert with our other results lead us to conclude that the phenotype of the "interferon-sensitive" mutant is more accurately described as ifp⁺. These findings provide a basis for further studies designed to reveal the nature of the IFN-inducer of is-l Mengovirus and the possible role of this type of particle and the interferon system in cell-virus persistence and the disease state.