Cellular proteins as potential targets for antiretroviral therapy.

The review article conducts an in-depth analysis of information gleaned from a comprehensive literature search across Scopus, Web of Science, and MedLine databases. The focal point of this search revolves around the identification and exploration of the mechanisms orchestrated by host cell factors in the replication cycle of the human immunodeficiency virus (HIV-1, Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus-1). The article delves into two primary categories of proteins, namely HIV dependence factors (such as CypA, LEDGF, TSG101) and restriction factors (including SERINС5, TRIM5α, APOBEC3G), providing illustrative examples. The current understanding of the functioning mechanisms of these proteins is elucidated, and an evaluation is presented on the potential development of drugs for treating HIV infection. These drugs aim to either inhibit or stimulate the activity of host factors, offering insights into promising avenues for future research and therapeutic advancements.

[Genetic diversity of capsid protein (p24) in human immunodeficiency virus type-1 (HIV-1) variants circulating in the Russian Federation].

INTRODUCTION: The human immunodeficiency virus (HIV) protein p24 plays an important role in the life cycle of the virus, and also is a target for diagnostic tests and for new antiretroviral drugs and therapeutic vaccines. The most studied variant of HIV-1 in the world is subtype B. In Russia, the most common variant is A6, the spread of recombinant forms (CRF63_02A6, CRF03_A6B) is observed as well as circulation of G and CRF02_AG variants. However, a detailed study of the p24 protein in these variants has not yet been conducted. The aim was to study the features of the p24 protein in HIV-1 variants circulating in Russia and estimate the frequency of occurrence of pre-existing mutations associated with resistance to lenacapavir, the first antiretroviral drug in the class of capsid inhibitors. MATERIALS AND METHODS: The objects of the study were the nucleotide sequences obtained from the Los Alamos international database and clinical samples from HIV infected patients. RESULTS AND DISCUSSION: The features of HIV-1 variants circulating in Russia have been determined. V86A, H87Q, I91F are characteristic substitutions in A6 genome. It is shown that the presence of preexisting mutations associated with resistance to lenacapavir is unlikely. CONCLUSION: Features of the p24 protein in HIV-1 variants circulating in Russia allow them to be distinguished from others variants and among themselves. The prognosis for the use of lenacapavir in Russia is generally favorable. The results obtained could be taken into account in developing and using antiretroviral drugs and therapeutic vaccines.

[HIV drug resistance: past and current trends].

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.

[Analysis of Tat protein characteristics in human immunodeficiency virus type 1 sub-subtype A6 (Retroviridae: Orthoretrovirinae: Lentivirus: Human immunodeficiency virus-1)].

INTRODUCTION: Tat protein is a major factor of HIV (human immunodeficiency virus) transcription regulation and has other activities. Tat is characterized by high variability, with some amino acid substitutions, including subtypespecific ones, being able to influence on its functionality. HIV type 1 (HIV-1) sub-subtype A6 is the most widespread in Russia. Previous studies of the polymorphisms in structural regions of the A6 variant have shown numerous characteristic features; however, Tat polymorphism in A6 has not been studied.Goals and tasks. The main goal of the work was to analyze the characteristics of Tat protein in HIV-1 A6 variant, that is, to identify substitutions characteristic for A6 and A1 variants, as well as to compare the frequency of mutations in functionally significant domains in sub-subtype A6 and subtype B. MATERIAL AND METHODS: The nucleotide sequences of HIV-1 sub-subtypes A6, A1, A2, A3, A4, subtype B and the reference nucleotide sequence were obtained from the Los Alamos international database. RESULTS AND DISCUSSION: Q54H and Q60H were identified as characteristic substitutions. Essential differences in natural polymorphisms between sub-subtypes A6 and A1 have been demonstrated. In the CPP-region, there were detected mutations (R53K, Q54H, Q54P, R57G) which were more common in sub-subtype A6 than in subtype B. CONCLUSION: Tat protein of sub-subtype A6 have some characteristics that make it possible to reliably distinguish it from other HIV-1 variants. Mutations identified in the CPP region could potentially alter the activity of Tat. The data obtained could form the basis for the drugs and vaccines development.

Highly prevalent Russian HIV-1 V3-loop sequence variants are susceptible to maraviroc.

INTRODUCTION: Maraviroc inhibits CCR5-tropic HIV-1 across different subtypes in vitro and has demonstrated efficacy in clinical trials. V3-loop amino acid variants observed in individual maraviroc-resistant viruses have not been found to be predictive of reduced susceptibility. Sequence-database searches have demonstrated that approximately 7.3% of viruses naturally encode these variants, raising concerns regarding potential pre-existing resistance. A study from Russia reported that combinations of these same amino acids are present in the V3 loops of the Russian variant subtype A (IDU-A, now A6) with a much greater prevalence (range: 74.4%-92.3%) depending on the combination. However, these studies and database searches did not include phenotypic evaluation. METHODS: Sixteen Russian HIV-1 isolates (including sub-subtype A6 viruses) were assessed for V3 loop sequence and phenotypic susceptibility to maraviroc. RESULTS: All 12 of the A6 viruses and 2/4 subtype B isolates encoded V3-loop variants that have previously been identified in individual virus isolates with reduced susceptibility to maraviroc. However, despite the prevalence of these V3-loop amino acid variants among the tested viruses, phenotypic sensitivity to maraviroc was observed in all instances. Similarly, reduced susceptibility to maraviroc was not found in virus from participants who experienced virologic failure in a clinical study of maraviroc in Russia (A4001101, [NCT01275625]). DISCUSSION: Altogether, these data confirm that the presence of individual or combinations of V3-loop amino acid residues in sub-subtype A6 viruses alone does not predict natural resistance to maraviroc and that V3-loop genotype analysis of R5 virus prior to treatment is not helpful in predicting clinical outcome.

[Analysis of HIV-1 (Human immunodeficiency virus-1, Lentivirus, Orthoretrovirinae, Retroviridae) Nef protein polymorphism of variants circulating in the former USSR countries.]

INTRODUCTION: The human immunodeficiency virus (HIV) Nef protein is one of the key factors determining the infectivity and replicative properties of HIV. With the ability to interact with numerous proteins of the host cell, this protein provides the maximum level of virus production and protects it from the immune system. The main activities of Nef are associated with a decrease in the expression of the CD4 receptor and major histocompatibility complex class I molecules (MHC-I), as well as the rearrangement of the cytoskeleton. These properties of the protein are determined by the structure of several motifs in the structure of the nef gene encoding it, which is quite variable. OBJECTIVES: The main goal of the work was to analyze the characteristics of Nef protein of HIV-1 variant A6, which dominates in the countries of the former USSR. The objective of the work was a comparative analysis of natural polymorphisms in the nef gene of HIV-1 sub-subtypes A6 and A1 and subtype B. MATERIAL AND METHODS: The sequences of the HIV-1 genome obtained during the previous work of the laboratory were used, as well as the reference sequence from GenBank. In this work, Sanger sequencing and new generation sequencing methods, as well as bioinformation analysis methods were used. RESULTS AND DISCUSSION: The existence of noticeable differences in the prevalence of Nef natural polymorphisms (A32P, E38D, I43V, A54D, Q104K, H116N, Y120F, Y143F, V168M, H192T, V194R, R35Q, D108E, Y135F, E155K, E182M, R184K and F191L), some of which are characteristic mutations for variant A6, was shown. CONCLUSION: Characteristic substitutions were found in the Nef structure, potentially capable of weakening the replicative properties of HIV-1 variant A6.

[Molecular epidemiological analysis of HIV-1 variants circulating in Russia in 1987-2015]. / Molekuliarno-épidemiologicheskii analiz variantov VICh-1, tsirkulirovavshikh v Rossii v 1987-2015 gg.

AIM: To simultaneously analyze HIV-1 samples from all Russian regions to characterize the epidemiology of HIV infection in the country as a whole. SUBJECTS AND METHODS: The most extensive study was conducted to examine nucleotide sequences of the pol gene of HIV-1 samples isolated from HIV-positive persons in different regions of Russia, with the diagnosis date being fixed during 1987-2015. The nucleotide sequences of the HIV-1 genome were analyzed using computer programs and on-line applications to identify a virus subtype and new recombinant forms. RESULTS: The nucleotide sequences of the pol gene were analyzed in 1697 HIV-1 samples and the findings were that the genetic variant subtype A1 (IDU-A) was dominant throughout the entire territory of Russia (in more than 80% of all infection cases). Other virus variants circulating in Russia were analyzed; the phenomenon of the higher distribution of the recombinant form CRF63/02A in Siberia, which had been previously described in the literature, was also confirmed. Four new recombinant forms generated by the virus subtype A1 (IDU-A) and B and two AG recombinant forms were found. There was a larger genetic distance between the viruses of IDU-A variant circulating among the injecting drug users and those infected through heterosexual contact, as well as a change in the viruses of subtype G that caused the outbreak in the south of the country over time in 1988-1989. CONCLUSION: The findings demonstrate continuous HIV-1 genetic variability and recombination over time in Russia, as well as increased genetic diversity with higher HIV infection rates in the population.

[Molecular epidemiological analysis of hiv infection in northern seaports of Russia].

The results of the molecular-epidemiological analysis of HIV-1 variants circulating in Arkhangelsk and Murmansk - northern seaports of Russia - were presented. In these seaports the HIV-1 variants belonging to subtype A1 were predominant (93% in Murmansk, 83% in Arkhangelsk). In addition to these variants, viruses of other subtypes such as B, C, D and recombinant forms CRF02_AG and CRF03_AB were identifed. The heterogeneity of circulating HIV-1 variants was higher in Arkhangelsk than in Murmansk. According to the results of phylogenetic analysis, subtype A1 sequences formed the common branch with nucleotide sequences of IDU-A strains found in other regions of Russia. HIV-1 variants of subtype B sub-clustered with sequences of East European B-variants. The recombinant strains CRF02_AG formed the common branch with HIV-1 sequences from Central Asia republics of the former USSR. Among 124 therapy-naive patients from Arkhangelsk and Murmansk (n = 124) the transmitted resistance was less than 5%.

[The analysis of sero-prevalence of virus of hepatitis E among patients with HIV-infection and syphilis.]

The infection with hepatitis E virus is one of causes of liver diseases in patients with secondary immunodeficiency, including HIVinfected ones. The study was carried out concerning analysis of rate of detection of serological markers of infection with hepatitis E virus in samples of blood serums of HIV-infected patients and other group of patients with expressed immuno-suppression - patients with syphilis. The sero-prevalence of hepatitis E virus on IgM-antibodies among HIV-infected patients in Moscow made up to 21.7% and 2.9% correspondingly. In the examined group from the Far-East region the highest sero-prevalence of hepatitis E virus on specific IgE-antibodies (73%) is established in the group of patients infected with HIV subtype B. The most frequently IgG and IgM antibodies to hepatitis E virus were detected in HIV-infected patients at the stage of disease 4B. The examined group of patients with syphilis the sero-prevalence of hepatitis E virus made up to 14.7% that significantly surpasses the given indicator in the group of healthy persons (1.7%). The increasing of the level of sero-postivity is demonstrated in the groups of patients with latent syphilis and on the second stage of disease. Therefore, the highest values of sero-prevalence of hepatitis E virus is observed in the groups of HIV-infected patients and patients with syphilis at late stages of disease. In the Russian Federation, the identification of antibodies to hepatitis E virus in HIV-infected patients depends of the region of residence.

[Genetic diversity of human immunodeficiency viruses and antiretroviral therapy]. / Geneticheskoe raznoobrazie virusov immunodefitsita cheloveka i antiretrovirusnaya terapiya.

The lecture is devoted to the analysis of the state-of-the-art of the impact of genetic diversity of human immunodeficiency (HIV) viruses on the pattern of infection and the efficiency of antiretroviral therapy (ART). It provides brief information on the origin and evolution of HIV and on the current classification of their genetic variants. The molecular epidemiological situation of HIV infection in Russia and nearby states and the major molecular HIV variants that are dominant in these countries, as well as their origin and prevalence trends are characterized. How the diversity of HIV can affect the efficiency of diagnosis, the transmission of the virus, and the pattern of HIV pathogenesis are briefly reviewed. The comparative data available in the world's scientific literature on these topics are given. More detailed attention is given to the possible causes of varying therapeutic effects against different HIV subtypes, as well as to the specific features of the formation and phenotyping manifestation of ART drug resistance mutations. There is evidence for the necessity of forming a unified follow-up system for treated HIV-infected patients during ART scaling, including in an effort to evaluate the impact of the specific features of the HIV genome on the efficiency of treatment regimens used in Russia.

Analysis of the env gene variability of the IDU-A HIV-1 variant in the outbreak of the HIV infection epidemic in Perm region of Russia (1996-2011).

In the present work, a total of 132 HIV-1 env gene C2-V3-C3 sequences belonging to the IDU-A genetic variant were analyzed. The variants were obtained from the viruses circulating among IDUs and heterosexuals in the Perm region at different periods. It was shown that the rate of the divergence of the IDU-A HIV-1 viruses from a common ancestor increased 4.3 times (p < 0.001) in 2011 as compared with the onset of the epidemics. The rate of the HIV-1 evolution was different in the two risk groups of the infection. The mean genetic distance of HIV-1 variants circulating among heterosexuals was 1.3 times longer (p = 0.008) than that among IDUs. The accumulation rate of the nucleotide (including nonsynonymous) substitutions in the C2-V3-C3 HIV-1 env gene region among individuals infected by heterosexual contacts was 1.7 times higher than that among IDUs. The differences in the positions of the codons subjected to positive selection were demonstrated depending on the infection risk group tested.

[Comparative analysis of genetic variants of the HIV-1 circulating in the Irkutsk region in 1999 and 2012].

The pol and env genome regions of the HIV-1 genetic variants circulating in the irkutsk region of russia in 1999 and 2012 were compared. The results of this work showed the dominance of the HIV-1 subtype a IDU-A genetic variant (100%) in this region. No primary resistance mutations in the pol gene in the treatment-naive patients were found. The heterogeneity of the viral population was found to be significantly increased based on the pol and env analysis among HIV-variants isolated in 2012 (12.88% and 2.16%) from the intravenous drug users as compared to HIV-variants that caused the outbreak of the HIV infection in 1999 (1.64% and 0.47%). In addition, the comparison of genetic distances of the pol and env gene sequences in the viruses isolated in 2012 from the HIV-positive persons infected through heterosexual intercourse and intravenous drug use demonstrated that the transmission route influenced the variability of the virus population. Among the viruses of IDU-A variant circulating in the area in 2012 the prevalence of X4-tropic variants was 24.7%.

[Molecular epidemiological analysis of HIV-1 in Kazakhstan in 2009-2013].

In this study pol gene analysis of 205 HIV-1 samples collected in Kazakhstan in 2009 and 2012-2013 was carried out. CRF02_AG variant is dominating in Almaty and actively circulates in East Kazakhstan Province. IDU-A variant is dominating in the rest of Kazakhstan. The data on low prevalence (3%) of HIV drug resistance mutations in native patients were obtained.

[Rapid spread of the HIV-1 circular recombinant CRF02-AG in Russia and neighboring countries].

The spread of the HIV-1circular recombinant CRF02-AG in countries of the former Soviet union (Commonwealth of Independent States, CIS) was studies using partial and full genome sequences. The full-genome sequence of the CRF02-AG recombinant circulating in Russia was obtained for the first time. A Global phylogenetic tree of CRF02-AG full-genome sequences was constructed. Three distinct groups of the sequences were detected as clustered by the geographical location (CIS, South Korea, and France), which is indicative of the single-virus introduction in each of the regions mentioned above. The CIS cluster exhibiting minimum genetic diversity was, therefore, relatively young. The phylogenetic analysis of the env gene sequences within the CIS cluster made it possible to clearly discriminate three branches: two of Russian and one of Uzbek origin. The low genetic diversity within the two Russian subclusters provides evidence of at least two recent independent introductions of the CRF02-AG recombinant from Central Asia into Russia. This work was performed within the framework of the 7th Federal Research Program (FP&), Project EURIPRED (European Research Infrastructures for Poverty Related Diseases), grant agreement No.312661.

[Molecular epidemiological analysis of the HIV infection in the Blagoveshchensk and Khabarovsk Area (Russian Far East)].

The results of the molecular-epidemiological analysis of the HIV-1 variants circulating in Blagoveshchensk and Khabarovsk (Russian Far East) were presented. In Blagoveshchensk HIV-1 IDU-A variants were dominated (92.5%), similar to the regions of the European part of Russia. In Khabarovsk the heterogeneity of circulating HIV-1 variants was noted. In addition to IDU-A variants (66.0%), the strains of subtype B (12.6%), C (4.4%) and recombinant strain form CRF02_AG (17.0%) were identified. Using the phylogenetic analysis method the version of the penetration of HIV-1 variants from China and Japan was not supported.

[HIV-1 genetic variants in the Asian part of Russia: a study (2005-2010)].

The HIV-1 genetic variants circulated in the Asian part of the Russian Federation in 2005-2010 were studied. The samples of HIV-1 (427 in total) were collected in Khabarovsk, Magadan, Kurgan, Krasnoyarsk, Noyabr'sk, Yakutsk, Altay, and Tyva. Sequencing of some genome regions followed by the phylogenetic analysis or specific Internet resource sampling were used as the main methods of the HIV subtyping. The domination of the IDU-A HIV-1 genetic variant typical of HIV-infection epidemic in Russia was shown in all regions tested in 2005-2010. This variant prevailed both in IDUs and heterosexuals. In addition to IDU-A, some other HIV-1 genetic variants were found among them: subtype B and recombinant CRF03_AB. The HIV-1 genetic polymorphism in Russia was found to be low. An increase in the genetic distance among studied de novo samples was noted in the Asian part of Russia in 2005-2010 (26-68%) as compared to the European variants in 1996-1999 (10%).

[Molecular genetic characterization of the HIV-1 variants abundant in Kirgiziia].

The results of the molecular epidemiological analysis of HIV-1 circulating in Kirghizia were presented. In the area of Kirghizia this type of the work was performed for the first time. Two main genetic variants were discovered: variant IDU-A dominating in the area of the former Soviet Union, as well as recombinant form CRF02_AG. The possibility of further recombination process between these two variants of HIV-1 was suggested.

[Analysis of the polymorphism of the genome region of HIV-1 encoding the fusion protein].

The prevalence of the mutations associated with HIV fusion inhibitor enfuvirtide resistance in Russia and CIS countries was studied. Enfuvirtide resistance mutations were not observed among studied viruses in Russia and CIS countries so far. It was found that high rate (35%) of natural polymorphism mutations were associated with enfuvirtide hypersusceptibility. It was also found that high frequency of accessory mutations N126K and E137K were observed in the HR2 region (27.5%). The accessory mutations in HR2 can contribute to increased resistance and improve viral fitness. Our data were compared with those obtained in similar previous studies.

[Molecular and epidemiology studies of HIV-1 prevalence in the Republic of Sakha (Yakutia)].

The gag, pol, and env genomic regions of HIV-1 variants currently circulating in the Republic of Sakha (Yakutia) were analyzed. The results of the study indicated that in this area there were HIV-1 variants belonging to two subtypes: A (IDU-A) and B, the former being predominant in this area and in the Russian Federation. The IDU-B-East strain was first isolated from a heterosexually infected patient, which suggests that the strain is outside the risk group of injection drug users. No cases of primary infection with resistant variants were notified during the study.

[Maternal and neonatal drug resistance].

The debatable article gives new evidence for the possibility, conditions, and resistance rate of the resistance to nevirapine, which results from its single use during labor for the prevention of vertical HIV transmission. The author analyzes the results of the 2009-2010 studies dealing with the use of high-sensitive methods for mutation detection, the impact of minor mutations on therapeutic effectiveness, and the evaluation of the effect of therapeutic support. She expressed the idea that it is expedient to test HIV for nevirapine resistance mutations in different periods after single administration of the drug as a prophylactic agent, the possible effects and algorithm of treatment if the above mutations are detected.