THE discovery of interferon suggested a new approach to the problem of curing virus diseases. Among the most effective chemotherapeutic agents in bacterial infections are the antibiotics which are the byproducts of microbial growth. It is therefore only natural to hope that some byproduct of viral growth might eventually be developed as an effective anti-viral substance. Many enzyme inhibitors can prevent viral multiplication in vitro but to date there are no unequivocally successful chemotherapeutic agents. Antibiotics have no effect on viral growth because they are directed against bacterial enzyme systems. Viruses, on the other hand do not have any enzyme systems and rely on those of the host-cell/virus complex. Consequently we are in the delicate position of having to find a substance which will inhibit the enzyme systems engaged in forming virus but which will have no deleterious effect on the normal cell enzymes. The ability of one virus to interfere with the growth of another was first described by Hoskins in 1935. Since then considerable attention has been directed to this property of viruses, culminating in the discovery of interferon in 1957. A second virus inhibitor, distinct from interferon, has since been found, and it seems likely that the property of viral interference is only an expression of the action of interferon and similar substances. The production of interferon is a property of the virus/host-cell reaction and although it tends to be specific for the cell species from which it was produced, protection of cell cultures from different animals is frequently obtained
Viral interference is usually taken to mean mutual exclusion, i.e., once a cell has been infected with one virus a second virus is prevented from entering and multiplying within the cell. Occasionally when two viruses are inoculated simultaneously neither will multiply. Although cells can be successfully infected with a variety of pairs of unrelated viruses this exclusion does occur and can be demonstrated in many ways, using intact living hosts or tissue cultures and live or inactivated viruses. The sequence of events is as follows. The host-cell system is inoculated with the interfering virus and a varying length of time is allowed to elapse before the addition of the second virus. Multiplication of this challenge virus is inhibited, due to the already present association of the host cell with the original virusIt appears that this interference is brought about by the production of the substance interferon by the infected cell but there is no complete proof of this as yet. Before discussing the production, properties and mode of action of interferon some brief mention will be made of the different ways in which interference phenomena can be observed. Interference has been demonstrated in the intact animal, the chick embryo and tissue cultures. A good example of this phenomenon in mice is the inhibition of Western Equine Encephalitis (WEE) virus by influenza virus. The influenza strain used in this experiment produces no disease in mice and appears to undergo only one cycle of multiplication in mouse brain. When a large dose of influenza virus is given intracerebrally, either before or at the same time as WEE the mice show no signs of illness. This high degree of protection against WEE lasts for about 7 days after inoculation of the influenza and then it gradually wanes until full susceptibility is restored at about the 21st day. An example of interference by killed virus is the protection of mice with U-V inactivated ectromelia virus. Mice inoculated simultaneously with a lethal dose of ectromelia virus and a massive dose of U-V inactivated ectromelia show little or no signs of infection and live virus cannot be isolated from sacrificed animals
Many interference effects can be observed in chick embryos infected with the Myxoviruses. In the case of influenza virus the addition of inactivated virus of the same or different strains before or after the inoculation of live virus markedly reduces viral production, and the degree of interference drops the longer the addition of the inactivated virus is delayed. One of the most important of the interference phenomena is the fall in virus yield when mumps virus is serially passed without dilution in the allantoic cavity. This is an example of autointerference. When undiluted mumps virus is inoculated the titre of the resulting virus is constant for several passages and then drops dramatically. Subsequent undiluted passage of this product results in repeated rises followed by drops in titre. The allantoic fluids of the passage which immediately precedes the fall in titre have a very high interfering capacity when tested against other viruses. Serial passage of diluted virus always results in a good yield of virus. This is important in the preparation of stock virus suspensions and applies to many viruses other than mumps. Examples of interference between pairs of related and unrelated viruses in tissue cultures have been described.5 Of these the most interesting is the resistance of various cell cultures, chronically infected with a variety of viruses, to re-infection with active homologous virus. When Newcastle Disease Virus (NDV) is inoculated into cultures of HeLa cells most of the cells are destroyed. The few remaining cells multiply and produce fresh cultures which are chronically infected with NDV. However, only one infectious unit of NDV is produced per 100 cells and the cultures cannot be destroyed by re-infection with active NDV, i.e., the same suspension as was used to infect the initial cultures. It has also been shown by other methods that the challenge virus can enter the cells and will multiply after prolonged incubation. The interference phenomenon is very common and can be demonstrated in all virus/host-cell systems. Probably interference always occurs but some viruses are more susceptible than others
It therefore seems that the long search for antiviral chemotherapeutic agents is at last beginning to show promise. The application of interferon to the treatment of viral infections is just commencing and much can still be expected from this approach, although a great deal will have to be done before antiviral agents are in regular effective use against those diseases caused by viruses.
