Vol 67, No 3 (2022)

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Full Issue


Enteral viral hepatitis in monkeys

Dogadov D.I., Kyuregyan K.K., Mikhailov M.I.


Within the last decade, a large number of viruses genetically related to human hepatitis viruses have been identified in different animal species, including monkeys. Numerous viruses related to human hepatitis A virus (HAV, Picornaviridae: Hepatovirus: Hepatovirus A) were detected in various mammalian species in 2015–2018, predominantly in bats and rodents, but also in shrews, seals and marsupials. Zoonotic hepatitis E virus (HEV, Hepeviridae: Orthohepevirus: Orthohepevirus A) genotypes have been found in wild boars, deer, camels, and rabbits, as well as in non human primates. In addition, viruses that are genetically close to HEV have been described in bats, ferrets, rodents, birds, and fish. Nevertheless, monkeys remain important laboratory animals in HAV and HEV research. The study of spontaneous and experimental infection in these animals is an invaluable source of information about the biology and pathogenesis of these viruses and continues to be an indispensable tool for vaccine and drug testing. The purpose of this literature review was to summarize and analyze published data on the circulation of HAV and HEV among wild and captive primates, as well as the results of experimental studies of HAV and HEV infections in monkeys.

Problems of Virology. 2022;67(3):173-184
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Enteroviral (Picornaviridae: Enterovirus) (nonpolio) vaccines

Novikov D.V., Melentev D.A.


Non-polio enteroviruses (NPEVs) are ubiquitous and are one of the main causative agents of viral infections in children. NPEVs most commonly infect newborns and young children, due to their lack of antibodies. In children, clinical manifestations can range from acute febrile illness to severe complications that require hospitalization and lead in some cases to disability or death. NPEV infections can have severe consequences, such as polio-like diseases, serous meningitis, meningoencephalitis, myocarditis, etc. The most promising strategy for preventing such diseases is vaccination. No less than 53 types of NPEVs have been found to circulate in Russia. However, of epidemic importance are the causative agents of exanthemic forms of the disease, aseptic meningitis and myocarditis. At the same time, the frequency of NPEV detection in the constituent entities of the Russian Federation is characterized by uneven distribution and seasonal upsurges. The review discusses the epidemic significance of different types of enteroviruses, including those relevant to the Russian Federation, as well as current technologies used to create enterovirus vaccines for the prevention of serious diseases.

Problems of Virology. 2022;67(3):185-192
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HIV drug resistance: past and current trends

Ozhmegova E.N., Bobkova M.R.


HIV infection is incurable, but effective antiretroviral therapy (ART) makes it possible to achieve an undetectable viral load (VL), to preserve the function of the immune system and to prevent the patient’s health. Due to the constant increase in the use of ART and the high variability of HIV, especially in patients receiving so-called suboptimal therapy for various reasons, the incidence of drug resistance (DR) is increasing. In turn, the presence of DR in an HIV-infected patient affects the effectiveness of therapy, which leads to a limited choice and an increase in the cost of treatment regimens, disease progression and, consequently, an increased risk of death, as well as transmission of infection to partners. The main problems of drug resistance, its types and causes, as well as factors associated with its development are considered. The main drug resistance mutations for each of the drug classes are described.

Problems of Virology. 2022;67(3):193-205
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Problems of specific prevention of African swine fever

Vlasova N.N., Verkhovsky O.A., Aliper T.I., Kapustina O.V., Alekseev K.P., Yuzhakov A.G., Gulyukin M.I., Gulyukin A.M.


This review presents the current state of the problem of development and application of the specific prevention of African swine fever (ASF) with a brief description of its etiology and pathogenesis. The unique nature of the ASF virus (ASFV) determines some limitations and the complexity of solving the problem of vaccine development. Such situation stimulated the development of highly specific diagnostic methods for rapid and accurate detection of the ASFV. In this regard, results of studies, including our own, concerning the comparative analysis of the genome of vaccine and virulent strains of the ASFV, as well as immunodiagnostic approaches to determine causes of high virulence and low protective activity of the ASFV, are briefly presented. Special attention is given to the issue related to the development of safe and effective vaccines against ASF. In this context disadvantages and possible advantages of live attenuated (LAV) and recombinant (RV) vaccines are considered in details. Results of recent studies on the assessment of the immunogenicity of genetically modified vaccines (GMV) which developed in various laboratories around the world are presented. The obtained data indicate that ASF vaccination is currently the most promising measure to stop the spread of this disease in our country and in the world, however, previous experience with ASF vaccination has revealed some problems in its development and application. The significant contribution of foreign researchers to the study of the basics of virulence of this pathogen and the study of its genes functions are noted. The possible further expansion of ASF in Europe and Asia in bordering Russia territories, as well as the established fact of the persistence of ASFV in wild boar population indicate a constant threat of its re-introduction into our country. In conclusion, the importance of developing a safe effective vaccine against ASF and the assessing of the possible risks of creating the artificial sources of the infection in nature as a result of its use is emphasized.

Problems of Virology. 2022;67(3):206-216
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Identification regulatory noncoding RNAs of human papilloma virus type 16 (Papillomaviridae: Alphapapillomavirus: Human papillomavirus) in cervical tumors

Kisseljova N.P., Fedorova M.D., Zaikina A.E., Elkina N.V., Goldobina E.E., Elkin D.S., Abramov P.M., Pavlova L.S., Vinokurova S.V.


Introduction. High carcinogenic-risk human papillomaviruses (hrHPVs) are recognized as etiological agents of cervical cancer. Constant expression of the viral oncoproteins, E6 and E7, is required for maintenance of the malignant phenotype of tumor cells. The exact mechanism of regulation of viral oncogenes expression in tumor cells is not fully elucidated.

The purpose: identification of viral noncoding RNAs (ncRNAs) in HPV16-positve cervical cancer.

Materials and methods. The reverse transcription polymerase chain reactions were used to detect viral ncRNAs in HPV16-positve primary cervical squamous cell carcinomas and SiHa and CasKi cell lines. The knockdown technique with oligonucleotides complementary to ncRNAs was used to elucidate their functions.

Results. We have identified ncRNAs transcribed in the upstream regulatory region of HPV16 in the cervical carcinoma cell lines and in 32 out 32 cervical squamous cell carcinomas with episomal or integrated forms of HPV16 DNA. Knockdown of sense or antisense strains of ncRNAs by oligonucleotides results in a decrease or increase of the E6 and E7 oncogenes mRNA levels in cells, respectively. These changes of oncogenes mRNA levels are accompanied by the modulation of the levels of the p53 protein, the main target of the E6 oncoprotein.

Conclusion. The presence of regulatory ncRNAs in all examined tumors and cell lines revealed for the first time indicates their necessity for maintenance of constant expression of E6 and E7 oncogenes in them. The findings can be useful for understanding of the fundamental aspects of the viral expression regulation in HPV16-positive tumors.

Problems of Virology. 2022;67(3):217-225
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Dwarf bat’s (Pipistrellus pipistrellus) lung diploid cell strains and their permissivity to orbiviruses (Reoviridae: Orbivirus) – pathogens of vector-borne animal diseases

Povolyaeva O.S., Chadaeva A.A., Lunitsin A.V., Yurkov S.G.


Introduction. Bat cell cultures are a popular model both for the isolation of vector-borne disease viruses and for assessing the possible role of these mammalian species in forming the natural reservoirs of arbovirus infection vectors.

The goal of the research was to obtain and characterize strains of diploid lung cells of the bat (Pipistrellus pipistrellus) and evaluate their permissivity to bluetongue, African horse sickness (AHS), and epizootic hemorrhagic disease of deer (EHD) viruses.

Materials and methods. Cell cultures of the dwarf bat’s lung were obtained by standard enzymatic disaggregation of donor tissue and selection of cells for adhesive properties. The permissivity of cell cultures was determined to bluetongue, AHL, and EHD orbiviruses.

Results. Diploid cell strains (epithelium-like and fibroblast-like types) retaining cytomorphological characteristics and karyotype stability were obtained from tissue of the bat’s lung. Their permissivity to viruses of the genus Orbivirus of the Reoviridae family, pathogens of transmissible animal diseases, has been established.

Discussion. The permissivity of the obtained strains of bat’s lung cells to bluetongue, AHL, and EHD viruses is consistent with the isolation of orbiviruses in bats of the species Pteropus poliocephalus, Pteropus hypomelanus, Rousettus aegyptiacus leachii, Syconycteris crassa, Myotis macrodactylus, and Eidolon helvum.

Conclusion. Strains of diploid lung cells of the dwarf bat are permissive to orbiviruses of bluetongue, AHS, and EHD, which allows us to recommend them for the isolation of these viruses, and the species Pipistrellus pipistrellus to be considered as a potential natural reservoir and carrier of pathogens of these vector-borne diseases.

Problems of Virology. 2022;67(3):227-236
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The analysis of immunoreactivity of individual B-cell epitopes of hepatitis C virus (Flaviviridae: Hepacivirus: Hepatitis С virus) NS4a antigen

Nikolaeva L.I., Belyavtsev A.N., Shevchenko N.G., Stuchinskaya M.D., Samokhvalov E.I., Dedova A.V., Sapronov G.V., Shastina N.S., Kuprianov V.V.


Introduction. Chronic viral hepatitis C (CHC) is a ubiquitous infectious disease, a significant limitation of which WHO attributes to the use of a new highly effective antiviral therapy. Previously, two B-cell epitopes were identified in NS4a antigen of the hepatitis C virus (HCV). It was shown that certain titers of antibodies (ABs) to the extended C-terminal epitope (1687–1718 a.a.) can predict a high probability of achieving a sustained virological response (SVR) to standard therapy with pegylated interferon-α and ribavirin.

The aim of the work was to determine immunoreactivity of two B-cell epitopes (middle and C-terminal) of NS4a antigen, and to estimate a possible association of ABs to them with the achievement of SVR after standard interferon therapy and treatment with direct antiviral drugs (DAAs) daclatasvir and sofosbuvir (velpanat).

Materials and methods. Blood serum samples of patients with CHC (n = 113), of which 55 participants received standard interferon therapy, 50 received velpanate treatment, the remaining 8 received no therapy were examined. The middle B-cell epitope (positions 24–34 a.a.) of NS4a was synthesized by the solid-phase method, while the C-terminal epitope (34–54 a.a.) was obtained using genetically engineered techniques. Enzyme immunoassay (ELISA) testing of the sera collected before treatment was performed for the two selected epitopes according to the conventional methods.

Results. The antibodies to the C-terminal epitope were detected significantly more frequently than those to the middle one (p = 0.01) when analyzing the blood sera of patients (n = 113). The presence of ABs to the C-terminal epitope in the serum samples of participants who completed standard interferon therapy was associated with the achievement of SVR (p = 0.0245). In the blood sera of participants who completed therapy with velpanate, an association of the presence of ABs to the C-terminal epitope with the achievement of SVR was also established (p < 0.0001). The presence of ABs to the middle B epitope was not associated with the achievement of SVR, regardless of the therapy used.

Discussion. The observed difference in the immunoreactivity of the two B-cell determinants may be associated with the localization of the nearest Th-epitopes, the sensitivity of NS4a antigen to proteolytic enzymes, and the peculiarities of epitope presentation by antigen-presenting cells. However, it should be noted that the immunoreactivity of the middle B-epitope is poorly studied. Although the association of ABs to the C-terminal epitope with the achievement of SVR has been shown by several scientific teams, the detailed molecular mechanism of their influence on the effectiveness of therapy is unclear.

Conclusion. In CHC, ABs to the C-terminal epitope of NS4a are produced more frequently than those to the median epitope. The presence of ABs to the C-terminal epitope is a predictive marker of a high probability of achieving SVR, regardless of the type of therapy and antibody titer.

Problems of Virology. 2022;67(3):237-245
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Epstein–Barr virus (Herpesviridae: Gammaherpesvirinae: Lymphocryptovirus: Human gammaherpesvirus 4) in Kalmyks and Slavs living in Russia: virus types, LMP1 oncogene variants, and malignancies

Gurtsevitch V.E., Lubenskaya A.K., Senyuta N.B., Dushenkina T.E., Smirnova K.V.


Introduction. The discovery of the Epstein-Barr virus types (Herpesviridae: Gammaherpesvirinae: Lymphocryptovirus: Human gammaherpesvirus 4) (EBV) – EBV-1 and EBV-2, which have different transforming abilities in vitro, stimulated the study of their prevalence in populations in order to elucidate the relationship with malignant neoplasms.

The aims of the work are to study the prevalence of EBV-1 and EBV-2 among representatives of 2 ethnic groups of Russia, Kalmyks and Slavs, sequencing analysis of the LMP1 oncogene in virus isolates, and analysis of the correlation between virus types and the incidence of certain forms of tumors.

Materials and methods. DNA samples were isolated from the biological material of oral swabs obtained from ethnic Kalmyks of the Republic of Kalmykia (RK) (n = 50) and Slavs, residents of the Moscow Region (MR) (n = 40). DNA samples were used to amplify EBV DNA, followed by determination of its concentration per 1 cell of washout, amplification of the LMP1 oncogene in viral samples, their sequencing, and determination of LMP1 protein variants.

Results. It has been established that with the same burden of EBV among representatives of both ethnic groups in the Kalmyk group, the ratio of persons infected with transforming and non-transforming types of the virus was almost the same (EBV-1 – 51%; and EBV-2 – 49%). Meanwhile, in the group of Slavs the transforming EBV-1 type virus dominated (80.6%). The predominance of EBV-1 type in representatives of the Slavs correlated with increased incidence of certain forms of tumors in the population of the MR when compared with similar values in the population of the RK, where both types of the virus were prevalent. Differences between the compared rates of cancer incidence were not statistically significant. Analysis of viral isolates showed a similar set of LMP1 variants in both ethnic groups.

Conclusion. In order to establish the influence of EBV types on the incidence of malignant tumors, additional studies involving representatives of various ethnic groups from different geographical regions are needed.

Problems of Virology. 2022;67(3):246-257
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