Interferon

Abstract

Interferon production is a host genome-controlled function, and follows the usual DNA to RNA to protein sequence. This function is ordinarily repressed, but is derepressed by virus infection and by other nonviral substances. It is not known if it is the viral protein or the viral nucleic acid that initiates the events which lead to depression. Interferon can also be released in vivo by at least one nonviral substance, bacterial endotoxin. Since neither RNA nor protein synthesis is needed in this latter case, it has been suggested that the interferon may exist in a preformed, possibly stored state, which can be rapidly mobilized if needed. The material released under these conditions exists predominantly in a form with a molecular weight approximating 100,000 as contrasted with the predominantely 30,000 molecular weight substance induced by virus infection. Actually, the molecular weight of interferon produced in vivo has turned out to be heterogeneous, ranging from about 18,000 to 100,000, with several of the inducers leading to the appearance of molecules or more than one molecular weight. In order for cells to develop resistance to virus infection upon treatment with interferon, the synthesis of RNA and protein is needed. This observation, coupled with the apparent fact that little or no interferon is absorbed by cells developing resistance to virus infection, suggests strongly that the interferon molecule per se is not the active antiviral substance, but rather that it induces the formation of a new substance which is actively antiviral. While the latter has been generally considered to be a protein, the data are equally consistent with its being an RNA. The development of an equilibrium between production and decay of this material in cells exposed to interferon may explain the steady-state antiviral condition of such cells. The available evidence indicates a near-absolute barrier to the antiviral action of interferon in cells of unrelated species. This species barrier is not complete in cells of related species. The results of a variety of experiments indicate that the interferon system affects a very early event in virus infection. No new viral nucleic acid is made. The parental strand of RNA, in at least one system, is prevented from being incorporated into ribonuclease-resistant, double-stranded form, presumably the replicative form. Also, in at least one system, interferon treatment prevents the association of the input viral genome with a 40S ribosomal subunit of the cell. This step is presumably the initial step in the development of the specific viral polysome which carries out the synthesis of virion components. The development of this specific viral polysome is blocked in interferon-treated cells. Cortisone and other steroid hormones interact in a variety of ways with systems producing interferon or developing an antiviral state consequent to treatment with interferon. Circulating interferon plays an early and important role in limiting the effectiveness of virus spread through the bloodstream to target organs. The prospects for practical application of the knowledge of the interferon'' system in controlling virus infections seem good for prophylaxis and hopeful for therapy. A relatively early evolutionary origin for the interferon system is indicated by its occurrence in mammals, birds, reptiles and fish. If the virus inhibitory phenomenon of plants and bacteria is demonstrated to be analogous to the interferon system of animals, then a truly primitive origin of this system will be indicated.