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AbstractInfection of mice with influenza A viruses led to the formation of clones of lymphocytes that specifically recognizes viral domains in the central zone of the NSP protein (amino acid positions 83–119). Computer analysis of the primary structure of the NSP protein showed the presence of T-cell epitopes in the central part of the NSP molecule. The findings indicate that the viral NSP gene is expressed in the infected animals and verify the concept of the bipolar strategy (ambisense strategy) of the influenza A virus genome.

•The tick-borne encephalitis virus Siberian subtype is currently dominant in Russia.•The vaccines are based on heterologous subtypes isolated 40–77 years ago.•Cytokine gene expression profile revealed Th2 mainly humoral immune response.•Cross-specific antibodies were detected in immunized mouse sera.•Maximal protection was afforded by the vaccine “Encevir” (“Microgen”, Russia). Among three main subtypes of the tick-borne encephalitis virus (TBEV), the Siberian subtype is currently dominant in a majority of the endemic regions of Russia. However, inactivated vaccines are based on TBEV strains of the heterologous Far Eastern or the European subtypes isolated 40–77 years ago. To analyze the efficacy of the available vaccines against currently prevailing TBEV isolates of the Siberian subtype, mice were immunized subcutaneously three times (one group per each vaccine). The expression of seven cytokine genes was determined using RT-PCR. Sera were studied using homologous and heterologous ELISA, hemagglutination inhibition (HI) and neutralization tests with TBEV strains of the Far Eastern, Siberian and European subtypes. Cross-protective efficacy of the vaccines was evaluated with the TBEV strain 2689 of Siberian subtype isolated from an ixodid tick from the Novosibirsk, South-Western Siberia, Russia in 2010. The cytokine gene expression profile indicates a predominantly Th2 response due to exogenous antigen presentation. Titers for homologous combinations of vaccine strain and strain in ELISA, HI and neutralization tests exceeded those for heterologous antigen-antibody pairs. Despite antibody detection by means of ELISA, HI and neutralization tests, the mouse protection afforded by the vaccines differed significantly. Complete protection of mice challenged with 100 LD50 virus of the Siberian subtype was induced by the vaccine “Encevir” (“Microgen”, Tomsk, Russia). The minimal immunization doze (MID50) of “Encevir” protecting 50% of the mice was less than 0.0016ml. Partial protective effect of vaccines produced in Moscow, Russia and Austria revealed MID50 within recommended intervals (0.001–0.017ml). However, the MID50 for the vaccine “Encepur” (Novartis, Germany) 0.04ml exceeded acceptable limits with total loss of mice immunized with vaccine diluted 32, 100 and 320 fold. These results suggest regular evaluation of TBEV vaccines in regions where heterologous virus subtypes prevail.

AbstractThe results of an electron microscopic study of the effect of heteropoly acids (HPAs) with a Keggin structure on particles of influenza A/Aichi/1/68 (H3N2) and A/California/07/09 (H1N1) pdm09 viruses are presented. It is shown that the action of HPAs on viral particles leads to a complete (or partial) removal of transmembrane glycoproteins and the destruction of matrix protein M1, which manifests itself in the deformations and destruction of viral membranes. Using the A/California/07/09 (H1N1) pdm09 viruses as an example, it is shown that the efficiency of the destruction of the viral envelope by HPAs depends on the medium in which the viruses are cultured. The mechanism of destruction is proposed, which involves the extraction of cholesterol, etching of phospholipids, and the formation of pores in the lipid membrane as a result of the action of heteropolyanions. It is assumed that the penetration of protons through the formed pores can lead to the destruction of the matrix protein M1.

AbstractThe effect of the drug Stimforte on infection by the Hepatitis C virus (HCV) has been studied. Stimforte partially inhibits HCV infection at a dose of 100 μg/mouse and almost completely at a dose of 300 μg/mouse within 24 h after administration of the drug. The mice sera resulting after 24 h in the presence of 100 and 300 µg/mouse of Stimforte effectively inhibit the production of HCV. Doses of 150, 200, and 250 µg/mouse are not effective. Stimulation of interferon-β (IFN-β) production is only observed at doses of 100 and 300 µg/mouse, which explains well the neutralizing capacity of the sera. The amount of IFN-γ also correlates well with the antiviral activity and neutralizing activity of mice sera. The drug practically does not stimulate production of IFN-λ. Thus, the neutralizing activity of sera and the antiviral activity are largely determined by the 1st and 2nd IFN groups.

AbstractStimforte in a wide range of concentrations (15–225 µg/mL) totally inhibits the cytopathic activity of hepatitis C virus (HCV) in the Vero-V cell culture. Interferons (IFN) play the most important role in the suppression of infection when the drug is introduced into the culture before the infection. When Stimforte is introduced after the infection, the mechanism of action seems to be different. The activators of IFN production are mainly (or exclusively) the ligands of receptor complexes TLR-4 and NOD-2 contained in the drug. The action of these substances is probably synergistic, similar to the action of LPS and MDP in Vero-V cells.

Stimforte, an immune response-stimulating preparation, is active with respect to hepatitis C virus (HCV) and herpes simplex virus type I (HSV-1). The effects of Stimforte in animals infected with either HCV or HSV-1 are fundamentally different. In mice with acute herpes virus infection, Stimforte administration leads to a higher activity of natural killer cells and cytotoxic lymphocytes, and the amount of interferon (IFN) λ grows. In mice infected with HCV, Stimforte administration results in a significant increase in IFN-β but not IFN-λ in blood and affected organs. Stimforte has been found to affect directly HCV reproduction that causes the infected cell death, but it does not affect HSV-1 reproduction in the Vero cells (V).

Biosensor based on long range surface waves on one-dimentional photonic crystal (PC) surface in microfluid channel was used to detect binding of cells, viruses, nanoparticles and proteins. Covalent attachment of biopolymers to polyaminated PC with glutaraldehyde cross-linking in microfluid channel results in functionally active proteins, living eukaryotic, bacterial cells and viruses. The evident advantages of the optical biosensor include native conformations of biopolymers, detection of reversible or permanent specific binding with ligands, broad detection scale from eukaryotic cells to low-molecular-weight ligands and observations in real time with possible calculations of affinity and kinetic constants. However, relatively low sensitivity limit near 0.1 μg/ml of proteins is significantly less those of ELISA and xMAP immunofluorescent analysis (approximately 1 pg/ml). Integral adlayer thickness does not reveal molecular events on each cell with possible variations. The label-free real-time optical detection allowed us to estimate cytotoxicity of currently used and novel drugs and to explore the antiviral properties of new compounds.

The cytotoxicity indices (IC50) of Keggin’s phosphorus-molybdenum heteropoly acids (HPCAs) and their sodium and potassium salts on dog kidney cells (MDSC) are determined. The antiviral activity of these compounds against topical strains of influenza A (H3N2 and H1N1) is revealed. The dependence of the biological properties of polyoxometalates on the elemental composition of their molecules is confirmed. It is shown that when some of the molybdenum atoms are replaced by vanadium atoms, HPCAs and their salts acquire higher cytotoxicities, which increase monotonically as the number of substitutions increases. For the first time, the dependence of the biological activity of HPCAs and their salts on the mass of cations is established and interpreted. The values of semilethal doses (DL50) of these compounds are established in vivo (on outbred white mice). The values of the toxicity index (TI) for aqueous solutions of HPCA sodium and potassium salts are determined in a wide range of concentrations (from 0.05 to 15 μM) on a model of motile cells. It is established that HPCAs and their salts are moderately dangerous toxic substances and have selective antiviral activity, which at low concentrations (less than 15 μM) for influenza A strains is manifested mainly by a decrease in hemagglutination activity.

We studied the effect of tilorone on the dynamics of IFNα, IFNγ, and IL-1β levels in the lung tissue and blood serum in relation to viral load in the lungs of BALB/c mice with pneumonia caused by influenza virus A/Aichi/2/68 (H3N2). Tilorone was administered per os in doses of 40, 150, and 540 μg per mouse 6, 30, and 78 h postinfection, which simulated the drug regimen used in the clinic for the treatment of influenza and acute respiratory viral infections in Russia and post-Soviet countries. Tilorone reduced viral load with the maximum amplitude (2-3 lg) after 1-2 administrations. The results of studying the dynamics of the cytokine levels in the infected animals in general support the previous hypothesis that, in repeated dosing, tilorone enhances the IFN response (compensates for its deficiency) at the early stages of acute respiratory viral infections and suppresses (damps) excessive production of IFN and proinflammatory cytokines at the later stages.

Immunogenic properties of synthetic peptides corresponding to regions 122–133, 136–147, 154–164, and 314–328 of the heavy chain (HA1) of A/Aichi/2/68 virus hemagglutinin were studied. Peptides 122–133 and 136–147 together form a nearly complete antigenic determinant A, peptide 154–164 is a part of determinant B, and peptide 314–328 corresponds to the C-terminal HA1 fragment. In a model influenza A/Aichi/2/68 infection in CBA mice, a protective effect of conjugates of BSA with peptides 136–147 and 314–328 was shown. Immunization of animals with conjugates BSA-(136–147) and BSA-(314–328) in combination with interferon inducers (larifan and ridostin) and a plant immunomodulator (immunomax) intensified the protection of mice against the influenza infection.