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В статье представлены результаты исследований ВИЧ-инфицированных пациентов на наличие резистентных штаммов. Выполнено 386 анализов за 2008-2019 гг. У 77,2% образцов выявлены мутации, отвечающие за резистентность ВИЧ. Наблюдается прирост пациентов с мутациями в геноме ВИЧ, отвечающими за резистентность к НИОТ+ННИОТ. Наибольшая доля «высокой» резистентности в группе нуклеозидных ингибиторов обратной транскриптазы принадлежит Lamivudine (3TC) и Emtricitabine (FTC), доля «высокой» резистентности в группе ненуклеозидных ингибиторов обратной транскриптазы - Nevirapine (NVP), Rilpivirine (RPV) и Efavirenz (EFV), в группе ингибиторов протеазы - Atazanavir (ATV) и Nelfinavir (NFV). Мутации L10I/F/V, Q58E в гене протеазы, отражающие генетическое разнообразие вируса, наблюдаются практически во всех образцах. Одновременное присутствие в образце L10I/F/V, M46I, I50L, A71V и I84V приводит к высокой устойчивости вируса к ингибиторам протеазы. При разборе клинических случаев выявляется зависимость приверженности к приему АРВТ и наличие мутаций, отвечающих за резистентность., The article presents the results of studies of HIV-infected patients for the presence of resistant strains. 386 tests were performed for period 2008-2019. 77.2% of the samples showed mutations responsible for HIV resistance. There has been an increase of patients with mutations in the HIV genome responsible for the resistance to NRTI+NNRTI. The largest share of "high" resistance in the group of nucleoside reverse transcriptase inhibitors belongs to Lamivudine (3TC) and Emtricitabine (FTC), the share of "high" resistance in the group of non - nucleoside reverse transcriptase inhibitors - Nevirapine (NVP), Rilpivirine (RPV) and Efavirenz (EFV), in the group of protease inhibitors-Atazanavir (ATV) and nelfinavir (NFV). Mutations of L10I/F/V, Q58E in the protease gene, reflecting the genetic diversity of the virus, observed in almost all samples. The simultaneous presence of L10I/F/V, M46I, I50L, A71V and I84V in the sample results in high resistance of the virus to protease inhibitors. The analysis of clinical cases reveals the dependence of adherence to ARVT and the presence of mutations responsible for resistance., Уральский Медицинский Журнал, Выпуск 4 (187) 2020

Replication of the HIV-1 virus requires reverse transcription of the viral RNA genome, a process that is specifically initiated by human tRNA3(Lys) packaged within the infectious virion. The primary binding site for the tRNA involves the 3' 18 nucleotides with an additional interaction between an adenine rich loop (A-loop) in the template and the anticodon stem-loop region of the tRNA3(Lys). The loop of the tRNA primer contains two hypermodified base residues and a pseudouridine that are required for a proper binding and activity. Here, we investigate the influence on the structure, dynamics and binding stability of the three modified residues (mnm(5)s(2)U34, t(6)A37 and Ψ39) using extensive molecular dynamics and Quantum Theory of Atoms in Molecules (QTAIM) analysis. Consistent with experiment, the results suggest that the three modified residues are required for faithful binding. Residues mnm(5)s(2)U34 and Ψ39 have a major influence in stabilizing the anticodon loop whereas mnm(5)s(2)U34 and t(6)A37 appear to stabilize the formation of the complex of tRNA3(Lys) with the HIV-1 A-loop.

Background The HIV pandemic is characterized by extensive genetic variability, which has challenged the development of HIV drugs and vaccines. Although HIV genomes have been classified into different types, groups, subtypes and recombinants, a comprehensive study that maps HIV genome-wide diversity at the population level is still lacking to date. This study aims to characterize HIV genomic diversity in large-scale sequence populations, and to identify driving factors that shape HIV genome diversity. Results A total of 2996 full-length genomic sequences from 1705 patients infected with 16 major HIV groups, subtypes and circulating recombinant forms (CRFs) were analyzed along with structural, immunological and peptide inhibitor information. Average nucleotide diversity of HIV genomes was almost 50% between HIV-1 and HIV-2 types, 37.5% between HIV-1 groups, 14.7% between HIV-1 subtypes, 8.2% within individual HIV-1 subtypes and less than 1% within single patients. Along the HIV genome, diversity patterns and compositions of nucleotides and amino acids were highly similar across different groups, subtypes and CRFs. Current HIV-derived peptide inhibitors were predominantly derived from conserved, solvent accessible and intrinsically ordered structures in the HIV-1 subtype B genome. We identified these conserved regions in Capsid, Nucleocapsid, Protease, Integrase, Reverse transcriptase, Vpr and the GP41 N terminus as potential drug targets. In the analysis of factors that impact HIV-1 genomic diversity, we focused on protein multimerization, immunological constraints and HIV-human protein interactions. We found that amino acid diversity in monomeric proteins was higher than in multimeric proteins, and diversified positions were preferably located within human CD4 T cell and antibody epitopes. Moreover, intrinsic disorder regions in HIV-1 proteins coincided with high levels of amino acid diversity, facilitating a large number of interactions between HIV-1 and human proteins. Conclusions This first large-scale analysis provided a detailed mapping of HIV genomic diversity and highlighted drug-target regions conserved across different groups, subtypes and CRFs. Our findings suggest that, in addition to the impact of protein multimerization and immune selective pressure on HIV-1 diversity, HIV-human protein interactions are facilitated by high variability within intrinsically disordered structures. Electronic supplementary material The online version of this article (doi:10.1186/s12977-015-0148-6) contains supplementary material, which is available to authorized users.