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Introduction: Molecular-genetic monitoring of human immunodeficiency virus (HIV) drug-resistant strains circulation as well as analysis of territorial peculiarities of different genetic variants prevalence of the virus is a crucial part of epidemiological surveillance over HIV-infection spread., Purpose: Objective of the research - to analyze the prevalence of HIV-1 genetic variants among HIV-positive people living in different constituent entities of the Far Eastern Federal District., Material and Methods: Molecular-genetic analysis of the Pol-gene that is coding protease and a part of reverse transcriptase of HIV-1 was performed for a total number of 206 blood plasma samples. The biological material was collected from HIV-positive people living in Sakhalin, Magadan and Amur regions, Jewish Autonomous District, Khabarovsk region, Republic of Sakha (Yakutia) and Chukotka Autonomous Region (constituent entities of the Russian Federation in the Russian Far East)., Results: The research demonstrated that HIV-1 sub-subtype A6 continues to be dominant and comprises 72.1±3.1% of all isolated subtypes in the regions of the Russian Far East. HIV-1 subtype B was identified in 14 cases (6.8±1.8%) and subtype C in 4 cases (1.9±1.0%). Spectrum of HIV-1 recombinant forms was determined for some regions. We identified five types of HIV-1 circulating recombinant forms (CRF): CRF03_AB - 2 (0.9±0.7%), CRF02_AG - 8 (3.9±1.3%), CRF63_02A1 - 27 (13.1±2.4%), CRF11_cpx - 1 (0.5±0.5%), CRF01_AE - 3 (1.5±0.8%). High heterogeneity of the virus was registered in the Jewish Autonomous District., Discussion: The conducted research revealed genetic differences in the landscape of HIV-1 subtypes circulation as well as differences in HIV-1 recombinant forms distribution frequency in the Russian Far East. Current findings are due to expansion of migration flows that promote cross-border importation and further spread of different HIV-1 genetic variants among population of the Far Eastern Federal District., Conclusion: The conducted research revealed that the molecular-genetic monitoring of HIV-1 genovariants should involve not only regions with high HIV-abundance but also with low HIV-prevalence and incidence., Competing Interests: The authors declare no conflict of interest.

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS) and leads to over one million of deaths annually. Highly active antiretroviral treatment (HAART) is a gold standard in the HIV/AIDS therapy. Nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT) are important component of HAART, but their effect depends on the HIV susceptibility/resistance. HIV resistance mainly occurs due to mutations leading to conformational changes in the three-dimensional structure of HIV RT. The aim of our work was to develop and test a computational method for prediction of HIV resistance associated with the mutations in HIV RT. Earlier we have developed a method for prediction of HIV type 1 (HIV-1) resistance; it is based on the usage of position-specific descriptors. These descriptors are generated using the particular amino acid residue and its position; the position of certain residue is determined in a multiple alignment. The training set consisted of more than 1900 sequences of HIV RT from the Stanford HIV Drug Resistance database; for these HIV RT variants experimental data on their resistance to ten inhibitors are presented. Balanced accuracy of prediction varies from 80% to 99% depending on the method of classification (support vector machine, Naive Bayes, random forest, convolutional neural networks) and the drug, resistance to which is obtained. Maximal balanced accuracy was obtained for prediction of resistance to zidovudine, stavudine, didanosine and efavirenz by the random forest classifier. Average accuracy of prediction is 89%.

A panel of 16 HIV-1 isolates was designed. Those isolates were isolated from patients undergoing HAART and developing resistance to the antiretroviral drugs. It was shown that the isolates were resistant to nucleoside RT inhibitors (retrovir, epivir) and non-nucleoside inhibitors (viramun). Isolates had stable replication activity. Average rate of cells expressing viral Ag was 14-20%. The infectious titer was 2.4 Ig TCID50. The sequencing showed that all isolates were of the subtype A dominating in the major part of Russian Federation. This panel could be used as the biotechnological base for studying antiretroviral drugs of new generation and for the design of experimental vaccines.

Here we describe a system based on recombinant lentiviral vectors for the safe screening of potential anti-HIV drugs. The system allows to evaluate the sensitivity of HIVl-1 reverse transcriptase and integrase (wild-type as well as mutant forms of these enzymes detected in drug-resistant virus isolates) towards different drugs and substances, but also to screen inhibitors of other stages of HIV-1 life cycle.

Influenza virus is a leading causing factor of infectious respiratory human pathology. The search and development of novel anti-influenza drugs with a wide spectrum of activity is an important goal for medical science. In addition to specific anti-viral activity of the compound, its way of application is of great importance. In this work, we present the results of the study of the activity of a combination of glutamyl-tryptophan with glycirrhyzic acid (GTGA) against oseltamivir-resistant strain of the virus A/Vladivostok/2/09 (H1N1) at per os application on the model of the lethal influenza infection in white mice. The application of the GTGA was shown to decrease the specific mortality of animals (index of protection 43-50%), to increase the mean day of death to 2.5-3.9 days, and to reduce the infectious titer of the virus in the lung tissue to 1.5-1.9 Ig EID50/20 mg. The corresponding values for the reference compound oseltamivir were 14-25%, 1.1-1.9 days and 0.7 Ig EID50/20 mg, respectively, depending on the dose of the virus. The use of the GTGA also led to a reliable increase of the titers of interferon in the blood from 44.3 to 66.3 ME/mL. Morphological analysis revealed that GTGA lead to normalization of the structure of the lung tissue restricting the level of the cytodestruction and inflammation. The results obtained in this work allow the combination studied to be suggested as a promising anti-influenza drug that is active against the drug-resistant virus strains and can be applied orally.

New adamantane derivatives with amino acid residues and other bifunctional compounds were synthesized and their antiviral activity towards influenza A(H1N1)pdm and A(H3N2) viruses was studied. Some of these adamantane derivatives completely suppressed replication of remantadine-resistant influenza A virus strains.

The review considers the chemical structure, pharmacodynamics and pharmacokinetics of telaprevir, a new direct-acting antiviral agent, used to treat patients with chronic hepatitis C (CHC). The given data on Phase II and III clinical trials enable the authors to state the high efficacy of the drug in patients infected with hepatitis C virus type 1. The paper also provides data on the resistance of telaprevir and its drug interaction and denotes the place of the drug in the current antiviral treatment of patients with CHC.

The paper gives the results of monitoring the circulation of influenza viruses in the 2010-2011 season, that covers the second year of circulation of pandemic A(H1N1)v virus strains, and their interaction with seasonal A (H3N2) and B strains. Unlike the previous season, the beginning of an increase in morbidity was recorded in January 2011; its peak in the most of contiguous areas was noted at 5-7 weeks of 2011, with its further decline to threshold levels at week 11 of 2011. Preschool and school children were most involved in the epidemic process. Three influenza virus strains (A(H1N1)v, A(H3N2), and B) were found to circulate. Differences were found in the level of participation of the isolated strains in individual areas of the Russian Federation. Detailed typing of the isolated strains determined the compliance of the vast majority of them with vaccine viruses. The pandemic influenza A(H1N1)v virus strains retained their susceptibility to oseltamivir and were resistant to rimantadine. The participation of non-influenza acute respiratory viral infection pathogens was estimated as follows: 11.9% for parainfluenza viruses, 5.9% for adenoviruses, and 3.5% for PC viruses, and 0.7% for pneumonia Mycoplasma, which was comparable with the previous epidemic seasons.

The paper gives concise data on the efficacy of entecavir in the treatment of chronic hepatitis B caused by its resistant virus strain and describes a relevant clinical case.

The presented clinical case gave rise to discussion of the main mechanisms and factors behind the progress of chronic hepatitis C. Special emphasis is laid on the currently available possibilities of antiviral therapy and its future prospects. The efficacy of personalized treatment and approaches to its improvement are considered based on the proper preventive measures and correction of factors responsible for poor responsiveness to the treatment, in the first place metabolic disorders (obesity, hepatic steatosis).

A study of the antiherpesviral activity of acycloguanosine (ACG) H-phosphonate (ACG-P) on a model of fatal herpesvirus infection in inbred BALB/c albino mice has established that ACG-P reduces death rates in the animals, considerably increases their average lifespan, and significantly decreases brain virus titers with both 60% mortality in the control and 92% mortality in the control group. There was also a significant inhibition of herpes simplex virus type 1 (HSV-1) replication in the brain tissue of animals receiving ACG-P on a model of ACG-resistant HSV-1/L2/RACG(TK-).

A number of new phosphoramidates of acyclovir--compounds of interest as anti-virals against resistant strains of virus herpes was synthesized. Several methods of synthesis of these compounds were suggested. Optimal method appeared to be the obtaining of phosphoramidates through the phosphomonocloride with its subsequent treatment with various amines. Two compounds have shown moderate activity against HSV-1.

The effect of meglumine salt of acridonoacetic acid (cycloferon) on the in vivo morphogenesis of influenza infection caused by viruses of different origin (avian, swine and human) and variable susceptibility to antivirals (rimantadine and oseltamivir) has been studied. The administration of cycloferon results in stimulation of the immune response, restriction of the foci of post-influenza pneumonia, and normalization of the structure of respiratory zones independently of the susceptibility or resistance of infectious virus to the drugs. Among virions formed in the lungs of cycloferon-treated mice, prevalence of irregular-shaped virions with defects of surface glycoproteins was observed. The data obtained suggest that cycloferon is a drug with the complex mechanism of activity.

Analysis of the experience gained during the last pandemic of 'swine' influenza A (H1N1) sw1 is presented with reference to clinical studies and etiotropic therapy. The mechanism of development of severe pneumonia as a result of mutations at the binding site of hemagglutinin receptor enhancing a2'-3'-sialoside specificity and pneumotropism of the virus is described. The data on the efficiency of Ingavirin, a new Russian antiviral for the treatment of influenza, are reported.

The paper presents the results of the first Russian experience in evaluating the sensitivity of the epidemic and pandemic influenza virus strains, circulating in the period 2009-2010, to the anti-neuraminidase drug zanamivir. A complex of studies, including enzyme immunoassay, fluorometric assay and partial sequence of the neuraminidases (NA1 and NA2) from influenza A virus strain, was applied. The findings Indicate that all the test strains, including those resistant to oseltamivir, were susceptible to zanamivir. The latter is recommended by the WHO for the prevention and treatment of influenza in pregnant women.

The antiherpesvirus activity of newly synthesized DNA-binding compounds for cultured Vero E6 cells was examined. The compounds were found to have selective antiherpesviral activity. Their antiviral activity was shown against the virus strains isolated from clinical specimens. The test compounds were ascertained to have also a high activity against herpes simplex virus type 1 (HSV-1/L2 TC-) that was very resistant to acyclovir. The authors' data demonstrated an obvious dose-dependent antiviral effect, which was representatively seen when Pt-bis-Dst and Lys-bis-Nt were used. The findings have offered the challenge to test some of these compounds in experiments on laboratory animals.

The study of the antiviral activity of Russian anti-influenza agents in the cultured MDCK cells demonstrated that arbidol and ribavirin inhibited the reproduction of various influenza A virus strains, including rimantadine- and ozeltamivir-resistant variants, as well as influenza B viruses (IC50 2-8.5 microg/ml). Rimantadine at concentrations of 1-5 microg/ml completely inhibited the reproduction of reference and ozeltamivir-resistant influenza A virus strains, and it had no effect on the reproduction of influenza B viruses and rimantadine-resistant influenza A viruses. Arbidol and ribavirin also inhibited the reproduction of pandemic influenza A/California/04/2009(H1N1), A/California/07/2009(H1N1), and A/Moscow/01/2009(H1N1)swl viruses in the cultured MDCK cells (IC50 = 1.5-4.0 microg/ml) while rimantadine had no effect on their reproduction. The cultured cells showed no significant antiviral activity of ingavirin at nontoxic concentrations (up to 200 microg/ml) against all study strains of influenza A and B viruses, including pandemic A(H1N1) influenza virus strains. The activity of rimantadine, arbidol, and ingavirin was found on a model of Influenza pneumonia in mice infected with their adopted influenza A/Aichi/2/69(H3N2) virus. The preventive efficacy of the three test agents was similar and most pronounced when they were used 96 hours before infection, by preventing 40-50% death in the animals and their body weight loss and by increasing their survival by 1.3-1.5 times. Arbidol and rimantadine were more effective when used for treatment and prophylaxis in doses of 30 and 10 mg/kg/day, respectively, by protecting the infected animals from 60-80% death, increasing their survival by 1.7-2 times, and preventing their body weight loss as compared with the control. The same experiments with ingavirin showed that this agent was less effective than arbidol and rimantadine. Thus, arbidol and rimantadine have a pronounced antiviral infection in both cell culture and a model of influenza pneumonia. The found efficacy of ingavirin on an integral model of murine influenza pneumonia without its activity in the cultured cells is likely to be due to other pharmacological properties of the drug rather than its direct virus-specific action.

The amino acid sequence of the known strain HXB-2 belonging to subtype B is used as a reference strain matrix to determine HIV genotypic resistance by the sequencing technique. However, numerous studies have ascertained that HIV non-B subtypes have been widely accepted in Russia. The authors' data show that the significance of low score mutations in the Russian populations of HIV-1 is yet to be explained, unquestionably, arouses great scientific interest, and calls for further study.

The ability of acycloguanosine H-phosphate to inhibit the reproduction of herpes simplex virus type 1 (HSV-1) variants, including its acycloguanosine (acyclovir)-resistant ones, was studied. Acycloguanosine H-phosphate-resistant HSV-1 variants were obtained. It was found that these variants were cross-resistant to thymidine kinase-dependent HSV reproduction inhibitors, but preserved sensitivity to Apa-A and phosphonoacetic acid.

The ViroSeq (Celera Diagnostics) and Trugene (Bayer HealthCare) HIV-1 genotyping systems are widely used today in world clinical practice to detect drug resistance mutations resulting from ineffective treatment for HIV infection. Only the former test has gained acceptance. The present study has compared ViroSeq and Trugene genotyping systems used to identify both mutations of drug resistance and those of polymorphism in the HIV variants circulating in Russia where the unique strain IDU-A prevails. Analysis of 18 samples from HIV-infected patients who received and did not receive specific therapy has demonstrated that the agreement of the results of the tests was 95% (180 of the 190 mutations). At the same time, the results of resistance mutation detection by the ViroSeq and Trugene HIV-1 genotyping systems coincided completely. The fact that the Trugene HIV-1 genotyping system may be used along with the ViroSeq test system in clinical diagnostic laboratories is shown in the paper.

In 2007-2008 in Russia, the epidemic upsurge of influenza morbidity was caused by the active circulation of influenza A(H1N1, A(H3N2), and B viruses. The center for Ecology and Epidemiology of Influenza studied 334 epidemic strains. The results of a comparative study of the svirus specificity of commercial test systems (AmpliSens Influenza virus A/B and AmpliSens Influenza virus A/H5N1) for the polymerase chain reaction diagnosis and virological assays, including virus isolation, revealed their high correlation, which confirms that they may be expensively used to monitor the circulation of influenza viruses in the Russian Federation. All the strains were isolated in the MDCK cell culture. Influenza A(H1N1) viruses (n = 127) were antigenic variants of the reference strains A/Solomon Islands/3/06 and A/Brisbane/59107. Influenza A(H3N2) viruses (n = 49) were antigenic variants of the reference strains A/Wisconsin/67/05 and A/Brisbane/10/08. One hundred and fifty seven Influenza B strains were drift variants of the reference strains B/Florida/4/06 and B/Shanghai/361/02 of lineage B/Yamagata/16/88 and one strain, a variant of Malaysia/2506/04 related to lineage B/victoria/2/87. The isolates interacted actively with human 0(I) blood group erythrocytes and much more weakly with chicken ones. All study influenza A(H1N1) viruses (n = 74) preserved their sensitivity to rimantadine while 24 (77%) of the 31 study influenza A(H3N2) virus strains were resistant. A study of the time course of changes in the generation of antibodies in the donor sera obtained in Moscow and the Moscow Region in different periods of the epidemic process revealed an increase in antibodies to the reference influenza A and B virus strains circulating in this period.

The paper presents the results of the first isolation of the new influenza virus in Moscow and the Russian Federation, which was similar to the swine A/IIV-Moscow/01/2009(H1N1)swl strain isolated on May 24, 2009 from a Russian arrived in Moscow from the USA on May 19, 2009. The antigenic, biological, and molecular genetic properties of this virus were studied. The virus was isolated on MDCK and chick embryos, the hemagglutination titers being 1:8-1:16 AE; the infectious titers being 6.51g of the tissue cytopathogenic infective dose (TCID50) and 7.01g of the common infective dose (CID50). The virus was sensitive to arbidol, ribavirin, oseltamivir, and resistant to rimantadine. The complete virus genome was sequenced; the data were accepted to the Gen Bank on May 28, 2009 under GQ219584-GQ219590 and GQ202724. The significant gene substitution of neuraminidase Asp for Gly in position 451, which has been undetectable in any other strain published in the Gen Bank by the present time is unique only to A/IIV-Moscow/01/2009 (H1N1)swl. The virus has been deposited in the State Collection of Viruses, D. I. Ivanovsky Institute of Virology, Russian Academy of Medical Sciences, under No. 2452 dated May 24, 2009.

Ingavirin is low toxic for the MDCK cell culture. The drug concentration of 1000 mcg/ml does not reach the CD50 value. The antiviral activity of Ingavirin was studied with respect to the influenza virus A/H1N1, including the Remantadin resistant variant, in 1-7 subcultutes. In multiple contamination by 0.01 CPD50/ml Ingavirin in concentrations of 250 to 400 mcg/ml prevented development of the virus-induced CPE. Analogous results were recorded with respect to the Remantadin resistant variant of the influenza virus A/H1N1. In the same concentrations the drug affected the virus reproduction, evident from inhibition of the hemagglutinin formation. No Ingavirin resistant mutants were isolated after the virus repeated subcultures in the presence of the increasing drug concentrations in the MDCK cell culture. In the experiment with multiple contamination by 0.01 CPD50/ml, the Ingavirin antiviral activity was detectable when the drug was administered 60 and even 90 min after the adsorption.

The study deals with the current topical problem in the development of a laboratory algorithm for the detection of early stages of HIV infection and for the creation of a monitoring system on this basis for the spread of drug-resistant HIV-1 strains. The paper presents the results of experimental examination of the most accessible health care methods for the differential diagnosis of early HIV infection, by using the test systems in Russia and gives practical recommendations on their application.

Investigations indicated that the epidemic upsurge of influenza morbidity in the 2005-2006 season in Russia was caused by the active circulation of influenza viruses A and B. The Center for Ecology and Epidemiology of Influenza, D. I. Ivanovsky Institute of Virology, Russian Academy of Medical Sciences, studied 182 epidemic strains. A hundred and thirteen influenza viruses A(H3N2) were similar to the reference A/California/07/2004 or were its antigenic variants. Thirteen influenza virus A(H1N1) strains that were antigenic variants of the reference A/New Caledonia/20/99 were isolated in sporadic cases. Influenza viruses B were similar to B/Malaysia/2506/2004--lineage B/Victoria/2/87). All the strains were isolated in the MDCK cell culture. Comparative study of the sensitivity of the chicken embryo (CE) and MDCK isolation system to the 1999-2006 epidemic strains showed that CE tropism was least pronounced in influenza viruses A(H3N2). Analysis of the 2002-2006 strains demonstrated that influenza viruses A reacted actively with human erythrocytes of the blood groups 0(I) and A(II) and very slightly with chicken ones. Eighty-five influenza virus A(H3N2) strains from the 2005-2006 epidemic season were investigated for rimantadine susceptibility. The frequency of rimantadine-resistant influenza virus A(H3N2) strains was 38.0%. Studies of 79 paired sera from patients revealed a rise of antibodies to influenza viruses A(H3N2) and B in 25.9-33.3 and 20.7-23.8% of cases, respectively. There was an increase in antibodies to influenza viruses A and B in the sera collected from donors in Moscow and its region in September 2005 to June 2006.

The study of the activity of arbidol against epidemic influenza A and B virus strains (2002-2005) in the cultured MDCK cells showed the higher sensitivity of enzyme immunoassay than that of hemagglutination test. The influenza A virus strains tested, including those resistant to rimantadine (5 microg/ml), were sensitive to arbidol (10 microg/ml). The population of influenza B virus strains was heterogeneous in this indicator, 43% of the strains being less sensitive to arbidol. There was an increase in the number of rimantadine-resistant influenza A(H3N2) virus strains (10-18%) in our country during 3 epidemic seasons. The sequencing analysis of protein M2-endoding gene revealed the amino acid replacement of serine by asparagine in position 31, which is characteristic of rimantadine-resistant strains. Arbidol in combination with rimantadine potentiated the effect of viral reproduction in the cultured cells, as compared with the effect produced by the same concentrations of the drugs used alone.

To study the regularities in the spread of drug-resistant HIV-1 strains among HIV-infected patients in the Southern Federal District (SFD), the HIV-1 pol gene site encoded for reverse transcriptase was sequenced in the samples taken from 22 HIV-infected SFD patients who received or did not receive antiretroviral therapy (ARVT). Analysis of the primary sequences of the HIV-1 pol gene in SFD patients untreated with antiviral agents revealed the absence of both primary and secondary mutations of resistance to a nucleoside reverse transcriptase inhibitor (NRTI) and a non-nucleoside reverse transcriptase inhibitor (NNRTI). The group of patients receiving antiviral treatment was found to have different drug resistance mutations in the HIV-1 pol gene: K70R, M184V, K219Q, T215Y/F, L74V, etc. Moreover, the patients on ARVT had higher CD4 T lymphocyte levels and higher immunoregulatory index in the presence of significantly lower HIV replication than the untreated patients. The authors make recommendations how to study HIV resistance in patients who are to be treated and are receiving ARVT and advise to monitor the spread of drug-resistant HIV strains in the SFD.

The review gives data on the reactogenicity, immunogenicity, and protective efficacy of the existing influenza vaccines, such as inactivated (conjugate, subunit, virosomal, cultural vaccines with adjuvants) and live vaccines, as well as on the new directions in the design of influenza vaccines. It also provides data on specific medications against influenza and discusses the problem associated with the occurrence of influenza viruses resistantto these drugs. The economic efficiency of the prevention of influenza with vaccines and drugs is under debate.

The epidemic upsurge of influenza morbidity in Russia in 2004-2005 was caused by the active circulation of influenza A(H3N2) and B viruses. A hundred and sixty-six epidemic strains were studied. All the strains were isolated in the MCK cell culture. Influenza A(H3N2) viruses (n=77) were antigenic variants of the reference A/Fujian/411/ 2002 and A/California/7/2004 strains. Three influenza A(H1N1) viral strains that were antigenic variants of A/New Caledonia/20/99 strains were isolated in sporadic cases. Influenza B virus strains (n=83) were antigenic variants of the reference B/Shanghai/361/02--lineage B/Yamagata/l6/88. In addition, 3 antigenic variants of B/Hong Kong/ 330/2002 (lineage B/Victoria/2/87) strains were isolated. Nine (20%) strains resistant to rimantadine at a concentration of 5 microg/ml were identified. Chromatographic analysis of B/Shanghai/361/02 and BIHong Kong/330/01 viral protein M1 trypsin hydrolysates revealed differences in the profiles of chromatograms of influenza A virus proteins M1. Examination of 121 pair sera from patients revealed an increase in antibodies to influenza A(H3N2) viruses in 10-21% of cases and to influenza B viruses in 20-36% of cases.

Current data concerning epidemiology, clinical picture, pathogenesis, prevention and treatment of Avian influenza H5N1, data of pharmacodynamics and pharmacokinetics of antiviral drugs--neuraminidase inhibitors and M2 channels inhibitors, also the recommendation of WHO for prevention prevalence of infection were discussed in the review. Strategic measures of WHO aims to protect humans from contact with infected poultry, in case of contact, to prevent transmission of this infection from human to human and occurrence of pandemic. Infected birds were the major source of the H5N1 influenza virus among humans in Asia. Mainly humans became infected by eating infected birds, by poor hygiene procedures when cooking infected birds, or by close contact with infected poultry. At present transmission of the H5N1 influenza from human to human by aerosol way hasn't been registered, but ongoing monitoring for identification mutation and adaptation of H5N1 influenza virus to human is needed. Season influenza and avian H5N1 influenza differ by the ways of transmission, clinical picture, severity, pathogenesis, response to treatment. Diagnostic of infection is difficult due to non-specific initial symptoms, in most cases disease begins with disturbance of under respiratory ways and in rare cases--from upper respiratory ways. High viral titre is identified in pharynx but not in nose. Initial symptoms of the H5N1 influenza are: fever greater then 38 degrees Celsius, mild cold, cough and shortness of breath, practically all patient have viral pneumonia, later secondary bacterial infection occurs, mild to severe respiratory distress, diarrhea, vomiting and abdominal pain. Conjunctivitis is rarely diagnosed contrary to season influenza. Sometimes gastrointestinal disorder begins a week early then respiratory symptoms. Complication also includes renal and multi organ failure. The cytokine storm is commonly developed during H5N1 influenza. For treatment and for prevention (under certain conditions) of the H5N1 influenza neuraminidase inhibitors such as oseltamivir (Tamiflu) and zanamivir (Relenza) are recommended. Currently circulatory of the H5N1 strains are fully resistant to an older class of antiviral drugs--the M2 channels inhibitors (amantadine and rimantadine). The knowledge of epidemiology, pathogenesis, clinical picture, treatment of the H5N1 influenza in humans, in spite of progress isn't complete. Future coordination of scientific investigation of the H5N1 influenza in humans should be provided not only in the countries where infection was revealed, but all around the world.

Studies indicated that the epidemic rise in the incidence of influenza was caused by its virus A (H3N2) circulation in Russia in the 2003-2004 season. The Center of Influenza Ecology and Epidemiology investigated 101 epidemic strains isolated the MDCK culture. Antigenic analysis showed that all viruses A(H3N2) were similar to the reference virus A/Fujian/411/02(H3N2) and only 5 strains slightly differed from the latter. Twelve (14%) strains resistant to rimantadine at a concentration of 0.5 mg/ml were identified. Investigation of paired sera from the patients demonstrated a rise of antibodies to the references of influenza virus A(H3N2) in 68.7% of cases and a less increase in those to influenza viruses A(H1N1) and B. The active circulation of A(H3N2) viruses was due not only to changes in their antigenic structure, but also to the low level of antibodies to these viruses, as shown by the analysis of donor sera.

A series of new 5-alkynyl-2'-deoxyuridines have been synthesized and their antiherpetic activity was tested in the cultured Vero cells on a model of herpes simplex virus type 1, including its acyclovir-resistant strains. Some test compounds were found to have a significant specific antiherpetic activity. Nucleoside XIV showed the greatest activity. Compounds IV and X also has displayed a significant activity against the herpes simplex virus type 1 strain that is highly resistant to acyclovir. Examining the combined action of substance II with acyclovir and ganciclovir has revealed a synergetic effect.

A total of 200 influenza A virus strains were studied. Among them there 32 strains of A(H1N1) and 84 strains of A(H3N2) from the 2002-2003 epidemic season and 84 strains of A(H3N2) from the 2003-2004 epidemic season. Most rimantadine-sensitive strains whose infectivity and hemagglutinating activity were found to decrease by the drug given at a concentration of 0.5 microg/ml. In terms of infectivity and hemagglutinating activity, the number of rimantadine-resistant strains of A (H1N1) was equal to 9.0% for A(H1N1) influenza viruses and to 10.0 and 14.0% for A (H3N2) influenza viruses in different seasons, respectively.

The anti-HIV activity of new membranotropic compounds, i.e. of the polycarboxylate matrix and of its derivatives modified by adamantane and norbonene, was studied in respect of HIV-1 strains, whose tropicity to coreceptors CCR5 and CXCR4 was different, as well as in respect of HIV-1 variants resistant to azidothymidine (AZT) in a continuous culture of human lymphoid cells (MT-4) and in mononuclear cells of peripheral blood from healthy donors. Testing of complex compounds in a culture of infected MT-4 human lymphoid cells showed an effective inhibition of viral reproduction of LAV.04 (CXCR4-tropic variant) and of HIV11(EVK) as well as AZT-resistant variants. The studied pharmacophores-modified compounds displayed, in infection of the primary culture of human mononuclear cells of the HIV-1 R5 and X4 strains, a notable antiviral activity with their HIV efficiency significantly exceeding the one of the original matrix.

In vitro selection of HIV-1(EVK) variants resistant to highly effective nucleoside reverse transcriptase inhibitors (NNRTIs), i.e. azidothymidine (AZT) and didanosine (ddI) was performed. In case of AZT resistant mutants, subcloning by limiting dilutions was used. The isolated AZT resistant mutants and subclones had a broad spectrum of phenotypic resistance (8, 25, 53, 80, 114, 160-fold). The ddI resistant mutant possessed 10-fold resistance. The AZT resistant mutants and subclones had a high level of cross-resistance to H-phosphonate of AZT (H-phAZT) and a moderate level of cross-resistance to d4T. Still, they were effectively inhibited by a new compound, i.e. phosphonate of d4T.

New water-soluble antiviral chemical agents, containing 10 to 30% of adamantane derivatives (amino-, aminopropyl-adamantane-, aminomethyl- and rimantadine), which were conjugated with polycarboxylic matrixes of the divinyl ether and maleic anhydride copolymers (DIVEMA), were developed. The polymeric drugs exhibited a low cytotoxicity (4 to 10 times less than rimantadine) and a wide spectrum of antiviral activity against influenza viruses, including both the remantadine-resistant strains of A/PR/8/34 (H1N1) and the B/Saint-Petersburg strain/71/77 as well as against herpes viruses of type 1, parainfluenza viruses of types 1 and 3 and RS-virus. A reduction of the viral infection titer in their reproduction in sensitive cells' cultures was more than 2.0 Ig ID50. Complete inhibition of viral-specific syntheses, registered by immune-enzyme assay (IEA) and by hemagglutination test was observed at low infection doses ranging from 1 to 100 ID50. The efficiency of the antiviral effect depends on a drug's molecular weight and a structure of chemical bonds between the adamantane nucleus and the polymeric matrix.

Analysis of molecular mechanisms of HIV-infection and targets for therapeutic intervention allowed to offer strategy for design of new effective anti-HIV/AIDS agents on the basis of two key principles: 1) intervention to infectious process beginning from the earliest stages of the virus penetration into cells; 2) blockade of not only one but several molecular targets of the HIV life cycle. The paper presents the results of the in vitro investigation of the anti-HIV activity (against several HIV-1 strains, including AZT-resistant ones) of new generation complex substances synthesized with application of the molecular substrategy for bifunctional inhibitors on the basis of a combination of nonspecific antiviral active polymeric anions with selective virus sensitive membranotropic pharmacophores of the adamantane and norbornene lines. The HIV-1 inhibiting potential of polymeric carboxylic acids (PKA) of various nature: synthetic polymeric analogues of succinic acid and carboxymethylated dextran was evaluated. It was shown that the antiviral action of PKA is located at the initial stages of HIV-1 penetration into cells and is markedly defined by balance of electrostatic activity and conformational mobility of the macromolecules. This corresponds to the evidence of the negatively charged macromolecules ability to bind the positively charged V3 loop within the viral protein gp120, preventing the HIV-1 adsorption on the surface of permissive cells. Chemical conjugation of the PKA with derivatives of the adamantane (amantadine and rimantadine analogues) or norbornene (related to deitiforin and natural bicyclic therpenoids) via spacer groups provides synergistic elevation of the anti-HIV-1 activity, first of all for the flexible chain PKA. The obtained result experimentally confirmed the theoretically predicted expansion of the anti-HIV-1 action of the bifunctional kind antivirals due to cooperation of the electrostatic potential of PKA with the virus specific hydrophobic activity needed to block postadsorption events of the HIV-1 life cycle, including both the virus penetration into cells and the virus posterity release from the infected cells. Additional cooperation of PKA with some special vectors targeted towards "Raft" domains of cellular membranes, epicentres for natural location of initial and completed stages of the HIV-1 replication cycle was also shown promising. The structure-function optimized samples exhibit high indexes of anti-HIV-1 selectivity up to IS50 = 10000.

The efficacy of monotherapy with one of the analogues of synthetic nucleosides (lamivudine) was studied in 22 patients with chronic viral hepatitis B (CVHB). The specific feature of the selected group was that there was no serum HBeAg, which is usually regarded as a sign of viral mutation. The time course of changes in the activity of blood and hepatic inflammatory processes and viral replication were studied at equal intervals. There was a direct correlation between the suppression of viral replication and the regression of activity indices, such as ALT, serological markers, DNA of viral hepatitis B, and the morphological constituents of the Knodell index) during lamivudine therapy. However, there were no substantial changes in the parameters of fibrosis throughout the treatment. Therapy resistance was revealed in 3 of the 22 patients with CVHV. Its basis was the mutation of hepatitis B virus in the YMDD-motive, which was detected in 2 of the 3 patients.

The effect of an original drug Kagocel on the reproduction of Herpes simplex virus including its mutant strains resistant to basic antiherpetic medicine Acyclovir was evaluated. Kagocel was shown to have a low cytotoxic effect on Vero cell and inhibited reproduction of Herpes virus type 1 and Herpes virus type 2 in noncytotoxic concentrations. Kagocel was also demonstrated to inhibit the reproduction of Herpes virus type 1, resistant to combination of Acyclovir and phosphonoacetic acid. Detection of direct antiherpetic activity of Kagocel in vitro opens good perspectives to its clinical application, especially in combination with Acyclovir, the medication with other antiherpetic mechanism of action.

The work deals with the molecular mechanisms of the development of resistance of HIV to modern preparations for treatment of HIV infection and AIDS: inhibitors of reverse transcriptase and protease. The principles and concrete schemes of the use of modern methods of geno- and phenotypic resistance determination of HIV are described in detail. The comparative characterization of both approaches together with the problems and difficulties connected with the interpretation of the results of resistance tests are presented, their probable clinical importance is discussed. Practical recommendations concerning the use of tests for the determination of HIV resistance under different clinical conditions, based on the conferences and literature data on HIV infection and for the period of 1999-2000, are reviewed.