Department of Molecular Virology

Cell Engineering Laboratory

Managed by Doctor of Biological Sciences, Professor A.A. Kushch.

The laboratory was established in 1986.

For the first time in our country, the laboratory staff developed a hybridoma technology for obtaining monoclonal antibodies (mAb) to viral antigens. The mAb panel for the surface antigen of the hepatitis B virus (HBsAg) was obtained and on its basis the first monoclonal test system was designed in our country for the diagnosis of hepatitis B. The introduction of the developed test system into production made it possible to significantly increase the sensitivity and specificity of the detection of the surface antigen of the hepatitis B virus in the blood serum and to reduce the incidence of post-transfusion hepatitis B.

Currently, the collection of hybridomas obtained in the laboratory includes more than 50 clones producing mAb that interact with proteins of the most common and epidemically significant viruses: hepatitis B and C viruses, herpes simplex virus, human cytomegalovirus, human immunodeficiency virus, tick-borne encephalitis virus, Venezuelan equine encephalomyelitis virus, avian influenza virus, and human influenza virus. Based on mAb, methods of detection and reagent kits have been developed for the detection of hepatitis B virus, hepatitis C virus, tick-borne encephalitis virus, human cytomegalovirus, herpes simplex virus, epidemic and pandemic strains of human influenza viruses. The priority nature of the developments is confirmed by copyright certificates for inventions and patents of the Russian Federation.

MAbs were also used to solve a number of theoretical issues. Using mAb, the fine antigenic structure and topology of the antigenic determinants of the studied viruses were determined, and previously unknown epitopes inducing the formation of virus-neutralizing antibodies and possessing protective properties were identified. The sites of integration of HIV proviral DNA on human chromosomes in HIV-infected cells have been established. The laboratory conducts research aimed at uncovering the cellular and molecular mechanisms of the development of hepatitis C.The effect of human cytomegalovirus on cell proliferation and apoptosis is being studied. Particular attention is paid to a new area in the laboratory's work: the development of DNA vaccines. Multi-epitope compositions have been proposed, the immunogenic and protective properties of two candidate vaccines have been studied: anti-herpes and anti-hepatitis C.A comprehensive study of the role of herpes viruses in the development of infertility, pregnancy disorders, and in the pathology of newborns is carried out.

Over the years of lab existence (1986-2015), the laboratory staff published 270 scientific papers, received nine copyright certificates for inventions, and six patents of the Russian Federation. The laboratory has trained 29 candidates and two doctors of sciences.

Laboratory of the structure and morphogenesis of viruses

Managed by Doctor of Biological Sciences, Professor A.A. Manykin.

The first head of the morphological laboratory at the Institute of Virology was Professor E.I. Turevich, who, while still a student at the University of Warsaw, worked at the department headed by D.I. Ivanovsky and carried out his first scientific work. E.I. Turevich made a significant contribution to the study of cell pathology in a number of viral infections, especially in rabies. After E.I. Turevich, for more than eight years the laboratory has been headed by Professor A.A. Avakyan.

From 1959 to 2016, the laboratory has been headed by Academician S.M. Klimenko. Electron microscopy has become the main research method. The laboratory uses the whole range of existing techniques for transmission and scanning electron microscope in the study of the morphogenesis of viruses, the structure of the virion, proteins and nucleic acids. Priority data have been obtained on the organization of DNA in the head of T-even phages, which to the maximum extent explain the mechanism of DNA ejection. For the first time, data were obtained on the organization of the ribonucleoprotein of the influenza virus into a coiled, integral structure containing all eight RNA segments.

In cooperation with the Laboratory of Virus Ecology, an indication was carried out within the family of many arboviruses isolated in the USSR, which made it possible to significantly accelerate the study of a number of viruses new to science. The participation of Academician S.M. Klimenko in these studies was marked with the State Prize of the Russian Federation in 1999.

The laboratory has made a significant contribution to the study of HIV infection. The core of the laboratory is high-level professionals — leading researchers E.A. Gushchina and A.A. Manykin. In the end of 2016, after Academician S.M. Klimenko passed away, the laboratory was headed by Professor A.A. Manykin.

In recent years, intensive research has been carried out using the in situ PCR method to detect papillomavirus type 16 and 18 DNA in cervical cancer biopsies and the hepatitis C virus genome in liver biopsies using in situ real-time PCR. Along with electron microscopy, the laboratory uses an atomic force microscope.

At different times, the laboratory staff defended four doctoral and 16 master's theses.

Virus Physiology Laboratory

Managed by PhD in Biological Sciences T.A. Timofeeva.

Until 1987, the laboratory was headed by Academician of the USSR Academy of Medical Sciences, director of the D.I. Ivanovsky Institute of Virology from 1961 to 1987, Viktor Mikhailovich Zhdanov. During this period, the scientific topics researched by the laboratory were very diverse. In the 1960s, the mechanisms of viral reproduction were studied, first by inhibitory analysis, and since 1967 — by molecular biological methods. During this period, replicative forms of RNA of paramyxoviruses were discovered and analyzed, with the direct participation of V.M. Zhdanov in experimental work, and virus-specific informosomes were described. In subsequent years, the range of models was significantly expanded. A large series of studies on mammalian oncoviruses was carried out, and an endogenous porcine virus was first discovered. The cellular origin of oncogenes of retroviruses was proved, studies of type D oncoviruses were carried out. Integration of the genome of non-oncogenic viruses (measles virus) was shown. During this period, the laboratory also conducted molecular biological studies of the hepatitis A virus.

Research on the human immunodeficiency virus (HIV), which has been actively pursued at the Institute of Virology since the early 1980s, was also started in the laboratory of viral physiology. In the course of these studies, a highly productive line of HIV-producing cells was obtained, the first diagnostic test system in the USSR was developed to detect the virus and antibodies to HIV, and laboratory production was organized for the release of the country's first batches of diagnostic kits. Later, the production was transferred to Novosibirsk, to NPO Vector, which has been producing the test system to this day.

For many years, starting in the 1960s, the laboratory has been studying the molecular biology of the influenza virus. In 1977, for the first time, the molecular biological characterization of the virus that caused the global epidemic of 1977 ("Russian flu") was carried out, and for the first time ever the antigenic variability of the virus when changing the host was shown. This area (molecular biology and molecular genetics of influenza viruses) has become the priority for the laboratory since 1987, when Professor N.V. Kaverin became the head of the laboratory after the death of V.M. Zhdanov. Since that time, work has been carried out in the laboratory to study the functional interaction of the genes of hemagglutinin and neuraminidase of influenza A viruses. For the first time, post-reassortational changes in hemagglutinin were described, which expanded the understanding of the evolutionary processes of influenza viruses. After the data on the three-dimensional structure of hemagglutinin of the H5 and H9 subtypes based on the results of X-ray crystallographic analysis were published, the laboratory for the first time ever performed a detailed mapping of the antigenic structure of hemagglutinin of these subtypes, which made it possible to identify the correspondence between the features of the distribution of antigenic regions and variations in the three-dimensional structure of hemagglutinin of various subtypes. After the emergence and spread of the 2009 H1N1 pandemic virus, the positions of amino acid residues recognized by monoclonal antibodies against the A/IIV-Moscow/01/09 (H1N1) pdm09 strain, the first 2009 pandemic strain isolated in Russia, were mapped in the Department of Ecology of Viruses of the D.I. Ivanovsky Institute of Virology. In addition to hemagglutinin mapping, a relationship was shown between such characteristics of the virus as antigenic specificity, virulence, and receptor activity. In our studies, for the first time, mapping of the protein regions of the influenza A virus nucleoprotein, which differ in different strains and are recognized by antibodies, has been carried out. For the first time, an antigenic site associated with a host circle has been identified in the influenza A virus nucleoprotein protein molecule. The localization and structure of the compact antigenic site of the nucleoprotein protein of the influenza A virus has been disclosed. The works performed in the laboratory have been published in leading Russian and international scientific journals and are widely cited in the scientific literature.

After 2010, one of the main areas of scientific activity of the laboratory under the leadership of Academician of the Russian Academy of Sciences N.V. Kaverin was associated with solving the problem of the ratio of variations in the antigenic structure of influenza A virus proteins and the evolution of the functional properties of viral proteins. The main objectives of the study were to identify the effect of mutations in the hemagglutinin of influenza A virus, which provide resistance to monoclonal antibodies, on the phenotypic properties of hemagglutinin, as well as to identify varying antigenic epitopes in the structure of the influenza A virus nucleoprotein protein.

After the death of an outstanding virologist and molecular biologist, Academician of the Russian Academy of Sciences Nikolai Veniaminovich Kaverin, the laboratory continues the cycle of these studies. The data obtained play an important role in understanding the processes of the emergence and adaptation of pandemic strains that acquire various combinations of genes from mammalian and avian influenza viruses, as well as the mechanisms of regulation of virulence and specificity of influenza viruses in relation to the host. Research on the use of reassortment of human and avian influenza viruses has been applied to obtain highly productive vaccine strains. They are directly related to the disclosure of the mechanisms of the influenza virus variability at the molecular level and are the most important achievement of Russian and world virology.

Immunochemistry Laboratory

Managed by Doctor of Biological Sciences, Professor E.V. Karamov.

The laboratory was created in 1995 at the D.I. Ivanovsky Research Institute of Virology under the leadership of Professor E.V. Karamov. Since that time, the laboratory staff have worked a lot to study the molecular and epidemiological characteristics of HIV-1 variants circulating in the territory of the Russian Federation and neighboring countries. Using the methods of comparative analysis of genetic sequences (genotyping) and the study of immunological properties (serotyping), HIV-1 variants circulating among drug addicts administering drugs intravenously identified in Russia, Ukraine, and Belarus were characterized. During the same period, the laboratory participated in the creation of the first domestic test system for the detection of HIV-1.

Research related to the prevention and treatment of HIV/AIDS is currently underway. Natural and synthetic compounds are being actively studied in order to create new anti-HIV drugs capable of suppressing HIV infection caused by viruses resistant to drugs used in treatment. The revealed low-toxic and highly efficient compounds are included in the Microbicides research program for the development of new immunobiological drugs designed to limit the sexual transmission of HIV. The second important direction in the laboratory's work is the development and evaluation of the efficacy of candidate anti-HIV/AIDS vaccines. One of the first domestic candidate anti-HIV vaccines "HIVREPOL", developed in cooperation with the State Research Center "Institute of Immunology" of the FMBA of Russia, has passed the 1st phase of clinical trials.

Laboratory of Genetically Engineered Drugs

Managed by Doctor of Biological Sciences L.I. Nikolaeva.

The laboratory was founded in 1986 under the leadership of Professor R.A. Gibadulin. The main area of work was defined as the creation of vector systems for the expression of recombinant viral antigens.

In the period from 1986 to 1996, modified vaccinia virus strains expressing the hemagglutinin group of the virus, HBs antigen of hepatitis B virus and a number of HIV-1 proteins were designed. Two authorship certificates and a patent were obtained for recombinant vaccinia strains synthesizing HBs-antigen of hepatitis B virus and HIV-1 Gag-Pol protein. The HBs antigen-producing strain was used in the production of a diagnostic test system at the NPO Vector (Novosibirsk).

In subsequent years, producer strains were constructed in a more promising system using the baculovirus genome as an expression vector in insect cell cultures Sf 21, Sf 9, Hi 5.

In the 2000s, strains producing various proteins of HIV-1 were designed, which made it possible to study individual stages of the morphogenesis of this virus and to establish the interaction of regulatory proteins Vif and Vpr with viral structural proteins and cellular structures. In collaboration with specialists from the George Washington University (USA), new data on the mechanism of interaction between the heat shock protein Hsp-70 of the cell and the regulatory protein Vpr of HIV-1 were obtained. In joint studies with the Laboratory of Leukemia Viruses of the Institute and the Laboratory of Immunology of Tel Aviv University, the development of an autoimmune response to the CD4 molecule in HIV-infected individuals has been shown.

Since 2006, under the leadership of Dr. L.I. Nikolayeva, the laboratory has been working on the production and analysis of recombinant proteins of the hepatitis C virus. Since 2009, studies have begun to analyze the role of the hepatitis C virus polymorphism and the IL28B gene in infected people. Together with the staff of the Faculty of Fundamental Medicine, Lomonosov Moscow State University, the role of polymorphism of eight more human genes in the development of liver fibrosis and the realization of the effects of antiviral therapy was analyzed. Currently, together with specialists from the Pirogov Russian National Research Medical University, the Department of Infectious Diseases of the Russian Medical Academy of Postgraduate Education, and the Center for Bioengineering of the Russian Academy of Sciences, research is being carried out to study the characteristics of the immune response to antigens of the hepatitis C virus.

Over the past five years, the laboratory staff published 14 articles in domestic and foreign journals, received a patent, wrote a manual, defended two Ph.D. theses.