[AVIAN RECOMBINANT VIRUS H5N1 INFLUENZA (A/VIETNAM/1203/04) AND ITS ESCAPE-MUTANT m13(13) INDUCE EARLY SIGNALING REACTIONS OF THE IMMUNITY IN HUMAN LYMPHOCYTES].

The innate immune receptors TLR4, TLR7, TLR8, and RIG1 recognized the structures of the influenza viruses in human lymphocytes and were activated by the recombinant avian influenza virus A/Vietnam/1203/04 and its escape-mutant m13(13) during early period of interaction. The stimulated levels are not connected with viral reproduction. Donor cells with the low constitutive immune receptors gene expression levels showed higher stimulation. Inflammation virus effects resulted in. increasing production of TNF-alpha and IFN-gamma by lymphocytes. Signaling gene reactions of the parent and mutant viruses endosomal as well as cytoplasmic receptors are very similar. The mutant virus A/Vietnam/1203/04 (HA S145F), stimulated an increase in the transcription level of the membrane receptor gene TLR4 and a decrease in the level of activation of TNF-alpha gene. Further studies of natural influenza virus isolates are necessary to estimate the role of HA antigenic changes on immune reactions in humans.

[THERAPEUTIC POTENTIAL OF ALPHA-INTERFERON PREPARATIONS DUR- ING SOCIALLY-SIGNIFICANT HUMAN DISEASES OF VIRAL ETIOLOGY].

Interferons (IFN) belong to key cytokines of innate and adaptive immune response and play an important role in anti-viral and anti-tumor protection. At the same time, they possess a pro- nounced immune-modulating, anti-proliferative and anti-fibrotic effect. A general comparative characteristic of human IFN type I (α/ß), IFN type II (γ) and IFN type III (λ) and nosological directionality of contemporary drugs created on their base is examined in the review. Epidemiologic parameters for main socially-significant human diseases of viral etiology are presented: influenza and other ARVIs, herpes infection, chronic viral hepatitis B, C and D. Main attention is given to analysis of effectiveness of therapeutic application of preparations based on IFNα during the in- dicated infections, a specter of main IFNα induced side effects is listed. Recent achievements on the path of creation of principally new drugs based on IFN, that have lower toxicity and higher clinical effectiveness, as well as perspectives of application of preparations based on recombinant IFN for therapy of potentially, dangerous diseases are examined.

[Usage of interferon inducers during viral infections].

Domestic researchers succeeded to create a group of original interferon inducers (II) with a high chemotherapeutic index and suitable for the prevention and treatment of viral infections and a number of other diseases. Clinical application of II concerns, first of all, a wide range of viral infections: influenza and other acute respiratory viral infections, herpes, hepatitis, encephalitis, rabies, slow and mixed infections, etc. The accumulated experience is generalized and the conclusion is made about the main advantages of II, which induce a balanced synthesis of endogenous interferon without antigenicity of its own. It is emphasized that a single injection of II "includes" synthesis of IFN in certain populations of cells and organs and provides a relatively long circulation of IFN at a therapeutic level and creation of long-term anti-virus resistance. It is concluded that, in general, interferon inducers with pronounced antiviral and immunomodulatory properties are currently used as effective tools for the prevention and treatment of a variety of diseases. The fact that II different in their chemical nature act at different stages of reproduction of viruses and affect various links of the innate and adaptive immunity explains the increased scope of the application of this group of drugs in medical practice.

[[Antiviral activity of the interferon beta 1a].

The antiviral activity of the interferon beta Ia was studied using the example of the antiviral activity of the drugs interferon beta Ia Genfaxon and Rebif for the influenza and herpes. A pronounced antiviral effect of the drugs against influenza and herpes viruses was-shown far the first time.

[Efficacy of polyprenyl phosphates in the experimental genital herpes model].

An experimental model of the primary genital herpes (herpes simplex type 2, HSV-2) in the female guinea pigs was suggested to study the infectious process activity of polyprenyl phosphates (PPP) and PPP+acyclovir (AC) complex treatment. The morphofunctional features of the guinea pig ovaries were studied in the control and experimental groups (the latter were inoculated with PPP and/or AC as a primary infection treatment) at the stage of the recurrent genital herpes aggravation. It was shown that in the case of combined PPP +AC use significant changes in the disease symptoms were observed, as well as a decrease in the infectious process activity and duration, and positive remote effect on the ovarian morphophysiology.

[Mathematic prognosis of cagocel effectiveness for prophylaxis and therapy of influenza].

The possibility of using a mathematic model of influenza epidemic in evaluation of effectiveness of an etiotropic preparation cagocel for prophylaxis and therapy of influenza as well as determination of possible damage from influenza epidemics and outbreaks in major cities of Russia is shown.

[Modern Russian Etiotropic Antiinfluenza Drugs].

Two main groups of the Russian etiotropic drugs recommended by the Ministry of Health of the Russian Federation for prophylaxis or treatment of influenza are described in the review, i.e. chemotherapeutics whose targets are various stages of the influenza virus reproduction and interferons and their inductors engaging innate immunity patterns.

[The therapeutic efficacy of cycloferon and the pharmacological activity of interferon inducers].

The review describes endogenous interferon inductors that belong to antiviral drugs and contain different chemical compounds. Among the groups identified by the authors, there are promising and most effective medicines inducing different types of interferon in the body, as well as their mechanism of action. The paper shows the synthesis of endogenous interferon and the level of its accumulation in the organs and tissues. The clinical effects of methylglucamine acridonacetate (cycloferon) are depicted in patients with major viral (influenza, acute respiratory viral and arboviral infections, and viral hepatitis) and bacterial (brucellosis, tuberculosis) infections, or endometrial hyperplastic processes. Cycloferon is shown to be used as an etiotropic and antipathogenic drug.

Ridostin induces transcription of a wide spectrum of interferon genes in human cells.

The effects of Ridostin on the transcription of IFN family genes in human fibroblasts and lymphocytes were studied by quantitative real-time PCR. The degree of gene induction by Ridostin was most pronounced in fibroblasts, and was significantly higher than the induction by Kagocel: transcription of IFN-ß, oligoadenylate synthetase, and double-stranded RNA-dependent protein kinase genes increased by about 2000, 100, and 20 times, respectively. In lymphocytes, Ridostin also activated a wide variety of IFN family genes, including genes of IFN-ß, IFN-γ, and IFN-dependent enzymes, but this induction was less pronounced than in the fibroblasts. It was shown that gene response in lymphocyte from a child with cancer is reduced in comparison with that of adult healthy participant. Ridostin, and even more so Reaferon up-regulated activities of ß-actin, glycerophosphate dehydrogenase, and ß2-microglobulin genes, thus making impossible or limiting their use as constitutive stable reference genes (standards) in PCR-assays of IFN and their inductors.

[Results and prospects of interferone inducers using in infectious diseases treatment].

There is represented the current classification of interferon inducers of various chemical groups related to antiviral agents, described the mechanisms of synthesis of different types of endogenous interferon in blood serum. The effectiveness of methylglucamine acridonacetates in integrated treatment of chronic hepatitis C, tuberculosis with HIV infection background, chronic brucellosis, arboviral diseases, including West Nile fever, as well as influenza and acute respiratory infections are shown. For successful treatment of acute and chronic diseases with endogenous interferon inducers should be applied as early as possible, at an average level of viremia , to enhance the effect of drugs with the directed etiotropic action and immunomodulators, which achieves the optimal pharmacotherapeutic effect.

[Virus infections and interferon inducers in the complex therapy].

Interferon inductors of various chemical groups, belonging to antivirals, and induction of several types of endogenous interferon in blood serum are described. Cycloferon was shown efficient in the complex treatment of chronic hepatitis C, tuberculosis in HIV-infected subjects, arbovirus diseases, influenza and acute respiratory virus infections.

In Vitro Antiviral Activity of a New Indol-3-carboxylic Acid Derivative Against SARS-CoV-2.

The coronavirus disease (COVID-19) pandemic has brought into sharp relief the threat posed by coronaviruses and laid the foundation for a fundamental analysis of this viral family, as well as a search for effective anti-COVID drugs. Work is underway to update existent vaccines against COVID-19, and screening for low-molecular-weight anti-COVID drug candidates for outpatient medicine continues. The opportunities and ways to accelerate the development of antiviral drugs against other pathogens are being discussed in the context of preparing for the next pandemic. In 2012-2015, Tsyshkova et al. synthesized a group of water-soluble low-molecular-weight compounds exhibiting an antiviral activity, whose chemical structure was similar to that of arbidol. Among those, there were a number of water-soluble compounds based on 5-methoxyindole-3-carboxylic acid aminoalkyl esters. Only one member of this rather extensive group of compounds, dihydrochloride of 6-bromo-5-methoxy-1-methyl-2-(1-piperidinomethyl)-3-(2-diethylaminoethoxy) carbonylindole, exhibited a reliable antiviral effect against SARS-CoV-2 in vitro. At a concentration of 52.0 µM, this compound completely inhibited the replication of the SARS-CoV-2 virus with an infectious activity of 106 TCID50/mL. The concentration curves of the analyzed compound indicate the specificity of its action. Interferon-inducing activity, as well as suppression of syncytium formation induced by the spike protein (S-glycoprotein) of SARS-CoV-2 by 89%, were also revealed. In view of its synthetic accessibility - high activity (IC50 = 1.06 µg/mL) and high selectivity index (SI = 78.6) - this compound appears to meets the requirements for the development of antiviral drugs for COVID-19 prevention and treatment.

[Discovery and scientific investigation of a biological phenomenon].

A brief discussion is devoted to the 55-year long history of interferons and the contribution of domestic researchers to the study of this problem.

[The problem of the use of interferons in the novel coronavirus disease COVID-19 (Coronaviridae: Coronavirinae: Betacoronavirus: Sarbecovirus)].

By the end of 2021, about 200 studies on the effect of interferons (IFNs) on the incidence and course of the new coronavirus infection COVID-19 (Coronaviridae: Coronavirinae: Betacoronavirus: Sarbecovirus) have been reported worldwide, with the number of such studies steadily increasing. This review discusses the main issues of the use of IFN drugs in this disease. The literature search was carried out in the PubMed, Scopus, Cochrane Library, Web of Science, RSCI databases, as well as in the Google Scholar preprint database using the available search queries «MeSH for coronavirus¼, «SARS-CoV-2¼, «IFN drugs¼, and «COVID-19¼. Interferon therapy is indicated for early administration (within the first 5 days of patient admission) in cases of mild to moderate COVID-19 to take advantage of the narrow therapeutic window of IFNs action. Control and suppression of viral replication requires therapy with IFNs and other effective antiviral agents that inhibit the reproduction of SARS-CoV-2 and induce several interferon-stimulated genes (ISG). Type I IFNs (IFN-I) exhibit potent pro-inflammatory properties and activate a wide variety of different cell types that respond to IFNs stimulation and pathogen entry. IFN-III confer local mucosal antiviral immunity without inducing the strong systemic pro-inflammatory responses associated with IFN-I. The use of IFNs drugs in the therapy of new coronavirus infection requires a cautious and differentiated approach, because in severe cases they can aggravate viral pathogenesis by causing excessive intensity of inflammatory reactions. The unique biological properties of substances of this class allow us to consider them as therapeutic agents with significant potential for use in patients with COVID-19.

[Adhesion molecules expressed in vascular endothelial cells in natural immunity against viral infections].

Cell adhesion molecules (CAM) expressed in vascular endothelium ensure integrity of the endothelial layer, recruitment and transmigration of leukocytes. Being receptors of many viruses, they play a role in immune control and infectious processes. Monoclonal anti-ICAM-1 antibodies enhance infection of primary human umbilical vein endothelial cell (HUVEC) cultures with HIV-1 due to incorporation into virions. IFN-gamma activates expression of ICAM-1 on HIV-infected HUVEC and thereby promotes binding of this molecule to complementary molecules on a greater number of sensitive cells, virion transfer onto them, and broad dissemination of the virus. Recombinant human IFN-alpha, IFN-beta and IFN-gamma influence (activate, inhibit) CAM shedding from HUVEC both intact and infected wit HSV-1. Activated shedding in the blood stream due to competition between soluble and endothelial CAM slows down recruitment and transmigration of leukocytes, i.e. regulates inflammation. CAM incorporated in microparticles can influence a wide spectrum of pathological processes Endothelial CAM may be a target for the delivery of pharmaceuticals for the treatment of vascular (including infectious) pathology.

[Problems in treating influenza and acute respiratory infection in children].

Results of an investigation of the efficiency of several antiviral medications in children are presented. Mechanisms of action of etiotropic chemotherapeutic medications are described. Interferons and interferon inductors are characterized and the results of clinical administration of classical interferon inductor cycloferon are reported. Detailed descriptions of immunotropic drugs recommended for use in children are presented.

[Cycloferon administration in chronic pyelonephritis: changes in interferon status].

AIM: To detect correlations between changes in interferon (INF) system and a course of chronic pyelonephritis (CP), to ascertain a corrective effect of cyclopheron in combined treatment with antibacterial drugs. MATERIAL AND METHODS: We examined 30 CP patients in different periods of the disease: group 1 had latent CP without laboratory evidence for exacerbation, group 2 had CP exacerbation treated with antibiotics, group 3 had exacerbation given basic treatment and cyclopheron by a standard scheme. All the patients were examined for interferon status, patients of groups 2 and 3 were examined once more after therapy. RESULTS: Patients of all the groups showed diminished ability of blood leukocytes to produce IFN, especially IFN-gamma. Cyclopheron addition to antibacterial therapy significantly stimulated production of IFN alpha and gamma by blood cells compared to basic therapy. Examination of 5 patients after 1-year follow-up detected preserved ability of blood cells to produce IFN and reduce the number of exacerbations after combined treatment with cyclopheron. CONCLUSION: Administration of cyclopheron in combination with standard antibacterial treatment results in persistent correction of IFN status.

[Interferon gamma in the treatment of patients with moderate COVID-19].

INTRODUCTION: Interferons are produced in response to the presence of pathogens in cells and are responsible for the proper formation of immune reaction. Preliminary data obtained in studies of properties of recombinant interferon gamma (IFN-γ) that involved patients with community-acquired pneumonia (including bacterial), acute respiratory viral infection (ARVI), influenza and new coronavirus infection have shown promising results.The purpose of the study was to assess the effect of subcutaneous administration of IFN-γ in patients with viral pneumonia on the changes of vital signs and the duration of hospital stay. MATERIAL AND METHODS: An open-label, randomized, low-interventional study included patients with moderate new coronavirus infection COVID-19 over 18 years of age of both sexes. IFN-γ 500,000 IU was administered s/c, daily, once a day, during 5 days. RESULTS: IFN-y in addition to complex therapy of the disease resulted in more favorable changes in the stabilization of vital signs, as well as in reduced length of fever and hospital stay by 2 days what allows suggesting a positive effect of this substance on the recovery processes in patients with moderate COVID-19. Special emphasis should be made to the fact that patients who received recombinant IFN- γ experienced no progression of respiratory failure and required no transfer to intensive care unit. DISCUSSION: This study confirms earlier obtained data on the positive effect of IFN-y on the rate of clinical stabilization and recovery of patients with community-acquired pneumonia and viral infections. Presented results are limited to a small number of patients; further study of drug properties in post-marketing studies is required. CONCLUSION: Progress in the treatment of patients with moderate COVID-19 by adding recombinant IFN-γ to the complex therapy may reasonably expand the range of existing treatment options for this infection.

[Interferons and other cytokines in patients with chronic pyelonephritis].

The article considers the modern views on changes in the cytokines system in patients with chronic pyelonephritis, which is one of the most common kidney disease. In this study we summarize data obtained by different researchers who assessed the role of cytokines for the diagnosis and prognosis of chronic pyelonephritis and for the application of antibacterial and immunomodulatory therapy of this pathology. We present results, that indicate changes in the interferon system of patients with exacerbation of chronic pyelonephritis under both standard antibiotic therapy and its combination with interferon inducers.

[Interferons and other cytokines in rheumatic diseases].

With the growth of rheumatic morbidity the spectrum of medicines for its management needs to be extended. Selected aspects of etiology and clinical course of rheumatic diseases are discussed with reference to prospects of their application for etiopathogenetic therapy.