[Dependence of the antiviral activity of the poly(G).poly(C) complex on the size of the continuous poly(C)segments]. / Zavisimost' protivovirusnoi aktivnosti kompleksa poli(G).poli(Ts) ot razmera nepreryvnykh uchastkov poli(Ts).

Modification of poly(C) by various frequency treatment with adenosine non-complementary to guanosine has produced poly(G) X poly (C.A) complexes with continuous double-stranded areas the length of which is determined by C/A ratio. Studies of the antiviral activity of poly(G).poly(C,A) complexes with C/A from 10:1 to 90:1 and poly(G).poly(C) in vesicular stomatitis virus-infected chick embryo cell cultures and in experimental tick-borne encephalitis of mice demonstrated that the maximum activity is achieved at an average lengths of double-stranded areas of 90 nucleotide pairs. At the same time, a low but statistically significant antiviral activity is observed at a length of double-stranded areas of 10-30 nucleotide pairs.

[Effect of the size of the continuous poly(G) site in poly (G, A).poly (C) complexes on their interferon-inducing activity and their capacity to stimulate the development of immunity]. / Vliianie razmera nepreryvnogo uchastka poli(G, A).poli(Ts) na ikh interferono-gennuiu aktivnost' i sposobnost' stimulirovat' formirovanie immuniteta.

It was established that the level of interferon-inducing activity of poly(G90A1).poly(C) complex in cell cultures and in mice was comparable to that of poly(G).poly(C). As the size of the continuous sites of poly(G) in the purine strand in poly(G, A).poly(C) complexes decreased to 60 and 28 nucleotides, the interferon-inducing activity decreased progressively, was still marked, or approached the zero at G:A ratios equal to 17:1 or 10:1, respectively. All this indicates that the cell receptors responsible for switching on of the induction mechanisms for interferon synthesis still recognize the stimulus 17 and possibly less so stimulus 10 of successively located guanosine nucleotides complementary to poly(C) and provide for the highest interferon production level when their number is equal to or exceeds 90-100. With the exception of poly(G10A1).poly(C) in which the interferon-inducing activity did not exceed its detection threshold, all complexes enhanced noticeably or markedly specific immune response in mice to tick-borne encephalitis after immunization with inactivated unadsorbed tissue culture vaccine against this infection. The level of this immunostimulating activity correlated irregularly with the intensity of their interferon-inducing activity.

[Evaluation of the size of the continuous poly(G) site necessary for the biological activity of the poly(G).poly(C) complex]. / Otsenka razmera nepreryvnogo uchastka poli(G), neobkhodimogo dlia biologicheskoi aktivnosti kompleksa (G).poli(Ts).

On the basis of synthesis of a series of poly(G, A).poly(C) copolymers with changing G:A ratio from 15:1 to 90:1 and trials of their biological activity in comparison with poly(G).poly(C), the size of poly(G) in it was evaluated within the range of a continuous double-stranded area necessary for the activity. The antiviral activity close to that of poly(G).poly(C) in experimental tick-borne encephalitis of mice and vesicular stomatitis virus infection of chick embryo cells was found only in poly(G,A).poly(C) complexes with a G:A ratio equal to or higher than 90:1. Consequently, the high activity of poly(G).poly(C) is present at an average length of poly(G) equal to 90-100 nucleotides within the limits of the continuous double-stranded area.

[Effect of virazole on the antiviral activity of poly(G) X poly(C) and other polyribonucleotide interferonogens]. / Vliianie virazola na protivovirusnuiu aktivnost' poli(G) X poli(Ts) i drugikh poliribonukleotidnykh interferonogenov.

The effect of virazole on the antiviral activity of poly (G) X poly (C), poly (G, A) X X poly (C) and poly(G, I) X poly (C) was studied in cell cultures and on mice. It was shown that virazole in concentrations not sufficient for significant inhibition of the development of vesicular stomatitis virus or Sindbis virus in chick embryo cell cultures markedly increased the antiviral effect and allowed decreasing the minimum effective doses of the synthetic polyribonucleotide complexes with respect to the above viruses. Combined administration of poly (G) X poly (C) and virazole to mice 1-2 or 24 hours after infection with tick-borne encephalitis virus provided a much more pronounced decrease in the death rate of the animals than the use of the interferonogen alone. Virazole per se was little active and had no significant effect on the intensity of interferonogenesis promoted by the use of poly (G) X poly (C). A possibility of successful therapy of viral infections with polyribonucleotide interferonogens in combination with virazole or other chemotherapeutic drugs with broad antiviral spectrum is discussed.

[Combined antiviral effect of synthetic polyribonucleotide interferonogens and specific antiviral antibodies in arbovirus infections]. / Kombinirovannyi protivovirusnyi éffekt sinteticheskikh poliribonukleotidnykh interferonogenov i spetsificheskikh protivovirusnykh antitel pri arbovirusnykh infektsiiakh.

A model of tick-borne encephalitis in BALB/c mice was used to investigate the protective anti-viral effect of an interferon inducer, poly(G).poly(C), and specific gamma-globulin administered to the animals together or separately in small doses 24 hours before or after virus inoculation. Administration to the animals of poly(G).poly(C) alone or gamma-globulin alone was shown to produce a poor protective effect. Simultaneous administration of both preparations resulted in a significant decrease of mouse mortality after infection. As a result of the pretreatment of chick embryo cell cultures with poly(G).poly(C) before inoculation and the addition of specific immune serum to the agar overlay after the Sindbis virus inoculation, its multiplication was inhibited much more than after treatment of the cells with interferon inducer alone or antibody alone. Possible mechanisms of the observed additive antiviral effects of the interferon inducer and antibody, including those associated with the influence on the virus-induced interferon production, as well as the possibility of their combined use for the prevention and treatment of viral infections are discussed.

[Effect of amphotericin B on the interferonogenic activity of poly(G) . poly(C) and poly(G,I) . poly(C) in mice and their resistance to infection by the tick-borne encephalitis virus]. / Vliianie amfoteritsina B na interferonogennuiu aktivnost' poli(G) poli(Ts), poli(G,I) poli(Ts) v organizme myshei i ikh rezistentnost' k zarazheniiu virusom kleshchevogo éntsefalita.

It was shown that amphotericin B, a polyenic macrolide markedly potentiated in mice the interferonogenic activity of the two-strand synthetic polyribonucleotide complexes, Poly (G) . Poly (C) and Poly (G, I) . Poly (C). At the same time amphotericin B used in high or low doses lowered or somewhat increased respectively the protective effect of Poly (G) . Poly (C) and Poly (G, I) . Poly (C) which was not adequate to the antibiotic effect on their interferonogenic activity. It was found that amphotericin B stimulated in the mice the infection caused by the forest spring encephalitis virus, accelerated the period of its manifestation and increased the death rate. This effect correlated with the concentration of amphotericin B and the dose of the virus. The relationship between the differential effect of amphotericin B on the interferonogenic and antiviral activity of polyribonucleotide interferonogenes and the stimulation of the viral infection by them is discussed.

[Concentrated purified vaccine against tick-borne encephalitis. An immunological evaluation in experiments on mice]. / Kontsentrirovannaia, ochishchennaia vaktsina protiv kleshchevogo étsefalita. Immunologicheskaia otsenka v opytakh na myshakh.

Comparative investigations of the immunological activity of two inactivated vaccines against tick-borne encephalitis, concentrated and commercial ones, were carried out. Higher levels of humoral and cellular immune responses were achieved after inoculation of the concentrated vaccine. Both vaccines did not affect the general immunological responsiveness of the animals.

[Effect of amphotericin B on the activity of synthetic polyribonucleotide interferon inducers]. / Vliianie amfoteritsina B na aktivnost' sinteticheskikh poliribonukleotidnykh interfeonogenov.

The authors investigated the intensity of interferon production and the degree of the associated antiviral resistance induced by double-stranded synthetic polyribonucleotide interferon inducers poly(G) . poly(C), poly(G, I) . poly(C) and poly(G, A) . poly(C) in chick embryo cell cultures, continuous diploid human fibroblasts and in mice in the presence of amphotericin B, a macrolide polyene antibiotic enhancing the permeability of plasma membranes for macromolecules. Amphotericin B was found to increase considerably the interferon-inducing and antiviral activity of the above polyribonucleotide complexes in those cell systems where they induced interferon production and antiviral resistance alone, without the antibiotic, but to a lower degree. Amphotericin B did not contribute to the activity of the complexes in those cell systems where they were inert alone. The importance of permeability of the plasma membrane for interferon induction is discussed, and a conclusion is reached that the inertness of the complexes under study in one cell system and their activity in the others are not associated with differences in the permeability of the plasma membranes of different cells for polyribonucleotide interferon inducers.

[Modification of the poly G-poly C complex by incorporation of adenosine in the purine chain]. / O modifikatsii kompleksa poli(G)-poli(Ts) vkliucheniem adenozina v purinovuiu nit'.

Antiviral and interferonogenic activity of the complexes of poly(G,A) . poly(C) and poly(G) . poly(C) was studied in mice and cell cultures. Three out of 4 complexes of poly(G,A) . poly(C) had insignificant antiviral and interferonogenic activity in chick embryo cells. One of the complexes induced low levels of interferon production in mice and decreased the rate of their death from experimental forest-spring encephalitis. The activity of poly(G) . poly(C) in the above cell systems was much more pronounced. Unlike this complex, some complexes of poly(G,A) . poly(C) showed a noticeable activity in the cells of Primates. The effect of the noncomplementary base in the purine thread of poly(G) . poly(C) on its biological activity and nucleotide composition is discussed.

[Increase in the specific activity of killed influenza vaccines by using polyene antibiotics]. / Povyshenie spetsificheskoi aktivnosti ubitykh grippoznykh vaktsin s pomoshch'iu polienovykh antibiotikov.

It was shown experimentally that polyenic antibiotics, i. e. amphotericin B and sodium levorin markedly increased the specific immunogenic properties and interferonogenic activity of inactivated influenza virus vaccine prepared with various methods from highly reproductive recombinants. The rate of pneumonia and death from influenza among the vaccinated mice treated with inactivated influenza virus vaccine and one of the polyenic antibiotics was lower than that among the animals treated with the vaccine alone (P less than 0.05). Correlation between the increase in the immunological response, the decrease in the virus reproduction rate in the lungs and addition of the antibiotics into the vaccine was also observed. It is recommended that inactivated influenza virus vaccine be used in conjunction with polyenic antibiotics.

[Effect of polyene antibiotics on the increase in specific resistance due to inactivated antiviral vaccines]. / Vliianie polienovykh antibiotikov na povyshenie spetsificheskoi rezistentnosti, vyzvannoi inaktivirovannymi protivovirusnymi vaktsinami.

The capacity of polyenic antibiotics, such as water soluble forms of amphotericin B, mycoheptin, nystatin and levorin to stimulate immunogenicity and interferonogenic activity of inactivated antiviral vaccines was shown. The protective effect of the vaccine against rabies or forest-spring encephalitis in albino mice was more pronounced on its two-fold use in combination with the antibiotic than that on its use alone. The most significant results were obtained with highly diluted vaccines supplemented with amphotericin B. In this case the resistance index was 2 times higher than on vaccination without amphotericin B. In comparative assays of 4 various lots of vaccines against rabies the ED50 of every inactivated vaccine corresponded to thrice as low levels of the antirabies antigen than on vaccination without the polyen. The problems of the mode of action of the polyenic antibiotics and antiviral inactivated vaccines used in combination are discussed.

[Effect of different polyribonucleotide interferonogens on acute and latent viral infections in mice]. / Vliianie razlichnykh poliribonukleotidnykh interferonogenov na ostruiu i latentnuiu virusnuiu infektsiiu myshei.

Poly(G) . poly(C) and poly(I) . poly(C) complexes administered soon after the viral challenge induced a high survival rate in mice with experimental tick-borne encephalitis. The protective effect was still noted when the treatment was given 24 hours after the infection. If the therapy was conducted at the end of the incubation period, at the peak of the virus reproduction in the mouse brain, poly(I) . poly(C) intensified the infection development and increased the animal death rate, while poly(G) . poly(C) had no such effect. Poly(I) . poly(C) injected 12 hours after the peak of the virus-induced interferonogenesis led to death of 80% animals inoculated with non-pathogenous Newcastle disease virus. The action of various samples of poly(I) . poly(C) was diverse. Poly(G) . poly(C) failed to effect the outcome of latent viral infection. The death of infected mice induced by polyribonucleotide complexes was not connected with their anti-viral interferonogenous activity, but correlated with the level of their toxicity for the intact animals. The results of the study have confirmed the risk of using poly(I) . poly(C) for the therapy of viral infections, especially during their clinical manifestation, and proved the safety of application of poly(G) . poly(C) and of some other polyribonucleotide interferonogens.

[Hydrolysis and the inactivation of double-stranded polyribonucleotides by monkey blood serum]. / Gidroliz i inaktivatsiia dvukhnitevykh poliribonukleotidov syvorotki krovi obez'ian.

The effect of Macaca rhesus monkey blood serum on double-stranded polyribonucleotide complexes poly (I).poly (C), poly (G).poly (C), and poly (G,I).poly (C) was studied. The poly (I).poly (C) complex was found to be the most sensitive to hydrolysis as indicated by a decrease of the molecular weight, accumulation of acid-soluble products and a sharp decline of the antiviral and interferon-inducing activities in tissue culture after incubation of the complex in the presence of the serum at 37 degrees C for 1 hour. The poly (G).poly (C) complex was the most stable, and retained its original activity in tissue culture and a high molecular weight after 3-hour incubation with the serum. The interferon-inducing activity of all the complexes under study assayed by intravenous injection in a dose of 2 mg to M. rhesus monkeys was similarly low irrespective of their sensitivity to the serum. Conjectural species features of the interferon induction system in monkeys are discussed.

[Interferonogenic activity of gossypol, a low-molecular substance]. / Interferonogennaia aktivnost' nizkomolekuliarnogo veshchestva gossipola.

The interferonogenic activity of gossipol, a low molecular substance of polyphenolic nature was shown in the cell cultures of chick embryos and organisms of mice. Pronounced prophylactic efficiency of the drug in mice with experimental infection caused by the West Nile virus was found. Definite parallelism between the intensity of interferonogenesis and the protection level from the virus affection due to the use of gossipol in mice was noted. Difference between gossipol and other known low molecular inductors of interferon, such as dyes, tyloron, propandinamine is discussed. The possibility of using gossipol as an antiviral drug is presumed.

[Comparative study of the toxicity of poly G-poly C and poly I-poly C in different objects]. / Sravnitel'noe issledovanie toksichnosti poli(G).poli(Ts) i poli(I).poli(Ts) na razlichnykh ob'ektakh.

The poly(G).poly(C) complex has the same interferon-inducing and antiviral activity upon parenteral administration to white mice as poly(I).poly(C), but is considerably less toxic. Upon intravenous inoculation of poly(I).poly(C) to mice its LD50 is 15.8 mg/kg whereas poly(G).poly(C) is not toxic in doses up to 200 mg/kg. In rabbits inoculated with poly(I).ploy(C) intravenously its LD50 is 0.22 mg/kg, while poly(G).poly(C) is not toxic in doses of 1 mg/kg. Histological examinations of different organs of mice and rats revealed no pathomorphological changes after a single intravenous and intraperitoneal inoculation of poly(G).poly(C). It exerted no embryotoxic effect in mice in a dose of 5 mg/kg and was considerably less toxic than poly(I).poly(C) in continuous diploid cell cultures of human embryo lung cells.

[Comparative antiviral and interferonogenic activity of synthetic polyribonucleotide complexes of poly(I).poly(C) and poly(G).poly(C) in different cell systems]. / Sravnitel'naia protivovirusnaia i interferonogennaia aktivnost' sinteticheskikh poliribonukleotidnykh kompleksov poli(I).poli(Ts) i poli(G).poli(Ts) v raznykh kletochnykh sistemakh

The antiviral and interferon-inducing activity of synthetic polyribonucleotide complexes poly(I)-poly(C) and poly(G)-poly(C) was studied in chick embryo, mouse embryo and rabbit kidney cell cultures. In chick embryo cell cultures both polyribonucleotides had similar antiviral activities. The interferon-inducing activity was more marked in poly(G)-poly(C) than in poly(I)-poly(C). In the other two cell cultures poly(I)-poly(C) was considerably superior in both activities. The revealed differences in the comparative activity of the polyribonucleotides in relation to the kind of tissue culture were not associated with differences between them in toxicity, sensitivity to pancreatic RN-ase or with possible differences in the duration of the contact with cells necessary for the achievement of the antiviral effect.

[Effect of interferon inducers on the development of specific resistance to tick-borne encephalitis]. / Vliianie induktorov interferona na formirovanie spetsificheskoi rezistentnosti k kleshchevomu éntsefalitu

Various natural and synthetic interferon inducers stimulate postvaccination immunity to tick-borne encephalitis virus in mice. This capacity was found not only in macromolecular synthetic polyribonucleotides such as (poly I)-(poly C), (poly G)-(poly C), (poly A)-(poly U) and substances with much lower molecular weight such as copolymers of vinylpyrrolidone with maleic anhydride, crotonic acid or metacrylic acid but also in a low molecular interferon inducer tiloron. These and other interferon inducers examined (endotoxin S-typhi, statolon) exhibited no parallelism between the intensity of their stimulating effect of immunogenesis and levels of interferon production induced in mice and the associated resistance to tick-borne encephalitis. The results indicate a possibliity of using various interferon inducers for stimulation of post-vaccination immunity to tick-borne encephalitis.