Adenovirus infection reverses the antiviral state induced by human interferon

HeLa cells treated with human lymphoblastoid interferon do not synthesize poliovirus proteins. The antiviral state against poliovirus is reversed if cells are previously infected with adenovirus type 5. A late gene product seems to be involved in this reversion, since no effect is observed at early stages of infection or in the presence of aphidicolin.     

Interferon-inducing and antiviral effects of inosiplex in combination with high-molecular interferon inducers

It has been shown that the immunostimulant inosiplex (IP) is capable of inducing interferon production in mice and of stimulating interferon induction by high-molecular inducers. The combined use of IP and poly (G)-poly (C) or dsRNA (RFf2) leads to a longer interferon circulation in the blood. All the combination schemes ensuring the effect of interferon production prolongation were tested for anti-viral activity. The prophylactic administration of the drugs permitted the attainment in mice of the increased resistance to experimental influenza.     

Comparative antiviral and interferonogenic activity of natural and synthetic interferon inducers in vitro and in vivo]

Biological activities of the RNA replicative form of phage f2, a natural interferon inductor and poly-I -- poly-C, a synthetic polyribonucleotide complex were studied comparatively. Differences in the comparative interferonogenic and antiviral activity of the inductors were as dependent on the type of the cell system. It was shown that DEAE-dextran increased the interferon-inducing activity of RFf2 in the cell culture by 4 to 8 times. The dynamics of the interferonogenic and antiviral activity of RFf2 in the L-929 cell culture was studied. Interferon appeared in the culture fluid in 6--8 hours and reached its maximum titers (128 IU50/ml) by the 24th hour, the maximum protection of the cells being also developed by the 12th--24th hour, reaching on an average 51 g PFU/ml. It was shown in the experiments with green marmosets that administration of RFf2 in the form of aerosol in a dose of 2.3 mg/kg induced interferon production in the blood serum the titers of which amounted to 80--160 IU50/ml 24 hours after the administration.     

Immunomodulating properties of interferon inducers

Data on the immunomodulating activity of interferon inductors are presented. It was revealed that the inductors increased the animal vaccinal response. Schemes for combined use of the interferon inductors and immunomodulators were developed. The immunomodulators were shown to increase the host interferon response evident from synergistic increasing of the interferon titers or prolongation of interferon circulation in blood of the animals. The efficiency of the schemes for combined use of the interferon inductors and immunomodulators was obvious from stimulation of the antibody production. As a result the time of the antibody circulation in blood increased. The effect of the combined use of the immunomodulators and interferon inductors was studied. The combined use of the preparations significantly increased the average life-span of the animals and the rate of their survival.     

Augmentation of mouse natural killer cell activity by interferon and interferon inducers.

Interferon (IF), in addition to its anti-viral capacity, is increasingly being found to be a regulator of cell division, cell surface antigens, and cell function. To determine whether IF also plays a role in the regulation of natural killer (NK) cell activity in mice, the in vivo and in vitro effects of IF and IF inducers on NK activity were studied. We observed that pyran, lipopolysaccharide, and polyinosinicopolycytidylic acid (poly I:C) as well as crude and purified IF preparations significantly elevated splenic NK levels in normal mice within 3 to 24 hr of i.p. administration. Normal spleen cells treated with poly I:C or IF in vitro also had augmented NK activity. Poly I:C and IF were themselves not cytotoxic and their presence was not required during the lytic process, indicating that IF acts on lymphocytes to activate NK function. The addition of anti-IF in the incubation medium completely blocked the boosting of NK activity by poly I:C or IF. The characteristics of the effector cells activated by IF were consistent with those of NK cells rather than macrophages, since the boosted effector cells were not retained by a rayon column or removed by carbonyl iron. Moreover, they were resistant to treatment with anti-Thy 1.2 serum plus complement, which eliminated mature T cells.     

Genotoxicity assessment of low-molecular weight interferon inducers by the SOS Chromotest

Tilorone and its aza-analogs, as well as CMA and its butyric analog (CNPA) were investigated as potential genotoxic agents by the SOS Chromotest. The SOS-inducing potency values (SOSIP) were 0.0033 and 0.0009 for SAF and vivakorfen, respectively, after activation with S9 fraction of mouse liver only. In contrast, an SOSIP value for tilorone of 0.0011 was observed in a non-activated assay. The SOSIPs of investigated compounds were low and comparable to the lowest values determined for other genotoxins. CMA and CNPA were not SOS inducers in any test system.     

Radiosensitizing effect of interferon synthesis inducers

The preinjection of inductors of leukocytic interferon synthesis of rapid (poly I.poly C, dextransulfate) and slow (tyloron) types to mice bearing inoculated solid sarcoma 37 considerably increases the efficiency of X-irradiation of tumors: the coefficient of tumor growth inhibition (kappa *) exceeds 1.0, and the number of animals with the completely regressed tumors increases. The effectiveness of the procedure depends on the time of the injection of the preparations and modes of irradiation.     

Optimization of the schemes for using interferon inducers

The results of study on 2 Soviet interferon inductors, i.e. the synthetic polyguacyl polynucleotide and natural double-strand phage RNA or dsRNA were studied. It was shown that the time course of accumulation and period of circulation of interferon depended on the route of the inductor administration. The antiviral activity of polyguacyl and dsRNA in experimental influenza and tick-borne encephalitis is described. The maximum protective effect with respect to experimental influenza was observed with intranasal administration of the drugs 4 hours before inoculation. A pronounced protective effect with respect to tick-borne encephalitis was observed with intraperitoneal administration of the inductors or their use in the form of aerosols. Direct correlation between interferon production and the final protective effect was found.     

Failure to induce an antiviral state in preimplantation bovine embryos treated with interferon

Bovine blastocysts hatched from their zonae pellucidae were cultured for 24 h in the presence or absence of interferon and then challenged with either vesicular stomatitis virus or bluetongue virus to assess the induction of an antiviral state. In contrast to its application to fetal bovine cells, where significant antiviral effects were induced, interferon treatment of embryos failed to reduce virus yield and had no effect on virus-induced cytopathology. This lack of biologic activity of interferon in bovine embryos is similar to that previously observed with undifferentiated murine embryonal carcinoma cells and is probably a manifestation of a more general mechanism regulating gene expression in the early mammalian embryo.     

Dissociation of protein kinase activity and the induction of the antiviral state in a cell line responsive to the antiviral effects of interferon

Interferons or oxidized glutathione were found to induce double-stranded RNA-dependent protein kinase activity in mouse L cells that phosphorylates the α subunit of eukaryotic peptide initiation factor 2. A mixture of leukocyte/fibroblast interferons as well as immune interferon induced the protein kinase and also suppressed virus replication in the L cells. Oxidized glutathione was equally effective in inducing protein kinase activity, but it did not induce an antiviral state in these cells. The data suggest that a simple cause and effect relationship does not exist between protein kinase induction and the establishment of the antiviral state in a cell that is responsive to the antiviral effects of interferon.     

Microinjection of anti-interferon antibodies into cells does not inhibit the induction of an antiviral state by interferon.

Affinity-purified polyclonal antibodies directed against human lymphoblastoid interferon (IFN), Escherichia coli-derived human IFN-alpha 2, or two synthetic fragments of human IFN-alpha 1 all neutralized the antiviral activity of human alpha IFNs when added to the culture medium of MDBK cells together with IFNs. However, when these antibodies were microinjected into the cytoplasm or the nucleus of cells, subsequent treatment of the cells with IFNs induced full protection against vesicular stomatitis virus. This suggests that IFNs themselves need not act in the cytoplasmic compartment or the nucleus to induce an antiviral state.     

Use of interferon inducers in treating viral diseases

The results obtained in the experimental and clinical study of the preparations of mephenamine acid and levamisole with respect to their interferonogenic and interferon-stimulating action and their therapeutic effectiveness in influenza and virus hepatitis are presented. The study has revealed that mephenamine acid, along with its capacity for stimulating the processes of interferon formation in the body, produces a pronounced curative effect, prevents the development of postinfluenza complications much more effectively than levamisole and remantadin and accelerates the processes of reparation in virus hepatitis.