[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.

[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.

Intestinal helminth infection impacts the systemic distribution and function of the naive lymphocyte pool.

Homeostasis is a fundamental principle of biological systems. A paradigm of immune homeostasis is the remarkably constant number of naive T and B lymphocytes in the body that continuously circulate through the secondary lymphoid organs to maximize immune surveillance. Whether the dynamics and distribution of the systemic naive lymphocyte pool is affected following organ-specific infection is not known. Here we show that, following infection of mice with an enteric helminth, naive T and B lymphocytes accumulate in the T helper type 2-reactive mesenteric lymph node while they are concurrently depleted from non-draining peripheral lymph nodes. This systemic redistribution of naive lymphocytes is sustained into the chronic phase of the infection, requires lymphotoxin beta receptor-dependent signals and is associated with a reduced ability of parasitized animals to mount antigen-specific cellular and humoral immune responses to heterologous immunization or infection at peripheral sites. Our data suggest that the function of the homeostatic naive lymphocyte pool can be modulated by its systemic distribution following infection and may provide a novel concept underlying compromised immune responsiveness at peripheral sites in helminth-infected individuals.

Tumor Necrosis Factor and Lymphotoxin in Regulation of Intestinal Inflammation.

Ulcerative colitis and Crohn's disease are the major forms of inflammatory bowel disease. Cytokines of the tumor necrosis factor (TNF) family play an important role in the regulation of intestinal inflammation. In this review, we discuss the function of key cytokines of this family - TNF and lymphotoxin (LT) - in mucosal healing, IgA production, and in control of innate lymphoid cells (ILCs), novel regulators of mucosal homeostasis in the gut. TNF plays a central role in the pathogenesis of inflammatory bowel diseases (IBD). LT regulates group 3 of ILCs and IL-22 production and protects the epithelium against damage by chemicals and mucosal bacterial pathogens. In addition, we discuss major mouse models employed to study the mechanism of intestinal inflammation, their advantages and limitations, as well as application of TNF blockers in the therapy for IBD.

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%.

Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells.

The immune mechanisms regulating epithelial cell repair after injury remain poorly defined. We demonstrate here that lymphotoxin beta receptor (LTßR) signaling in intestinal epithelial cells promotes self-repair after mucosal damage. Using a conditional gene-targeted approach, we demonstrate that LTßR signaling in intestinal epithelial cells is essential for epithelial interleukin-23 (IL-23) production and protection against epithelial injury. We further show that epithelial-derived IL-23 promotes mucosal wound healing by inducing the IL-22-mediated proliferation and survival of epithelial cells and mucus production. Additionally, we identified CD4(-)CCR6(+)T-bet(-) RAR-related orphan receptor gamma t (RORγt)(+) lymphoid tissue inducer cells as the main producers of protective IL-22 after epithelial damage. Thus, our results reveal a novel role for LTßR signaling in epithelial cells in the regulation of intestinal epithelial cell homeostasis to limit mucosal damage.

[Contribution of microbiologists of Kirov City to development of penicillin and streptomycin production processes (70 years since development of technology for submerged production of first domestic antibiotics)].

The publication is concerned with development of the technological processes for submered production of the first domestic antibiotics 70 years age. The literature data on the contribution of the microbiologists of the Kirov City and mainly the workers of the Red Army Research Institute of Epidemiology and Hygiene (nowadays Central Research Institute No. 48 of the Ministry of Defense of the Russian Federation, Kirov), to development of the manufacture processes for production of penicillin and streptomycin are reviewed.

[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.

[Influence of perfluorodecalin on growth of actinomycetes and intensification of Streptomycin and daunorubicin production by the genus Streptomyces kind bacteria in submerged culture].

Addition of perfluorodecalin with gas-transporting function to the liquid medium during submerged cultivation of actinomycetes of the genus Streptomyces resulted in higher intensity and level of the biomass synthesis and increased production of streptomycin and daunorubicin. Addition of perfluorodecalin to the medium provided a 2.0-2.3-fold surpass of the maximum antibiotic production (achieved by the 120th-144th hours of the culture growth) vs. the antibiotic accumulation peaks in the control.

[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%).

[Effects of waste water sediments on the levels of heavy metals ion the soil and plants]. / Vliianie osadkov stochnykh vod na soderzhanie tiazhelykh metallov v pochve i rasteniiakh.

Field small-plot experiments studied the effects of sediments of waste water from Saransk disposal systems. The content of toxic heavy metals (lead, arsenic, and cadmium) in the waste-water sediments, was shown to be not greater than their maximum permissible concentrations (32, 2, and 10 mg per kg of dried soil, respectively). With the use of waste-water sediments, the content of manganese, copper, tin, nickel, vanadium, beryllium, cobalt, iron, and chromium was found to correspond to their baseline level in the soil and plants.

Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1.

Amyloid beta (Abeta) is a major contributor to the pathogenesis of Alzheimer's disease (AD). Although Abeta has been reported to be directly neurotoxic, it also causes indirect neuronal damage by activating mononuclear phagocytes (microglia) that accumulate in and around senile plaques. In this study, we show that the 42 amino acid form of beta amyloid peptide, Abeta(42), is a chemotactic agonist for a seven-transmembrane, G-protein-coupled receptor named FPR-Like-1 (FPRL1), which is expressed on human mononuclear phagocytes. Moreover, FPRL1 is expressed at high levels by inflammatory cells infiltrating senile plaques in brain tissues from AD patients. Thus, FPRL1 may mediate inflammation seen in AD and is a potential target for developing therapeutic agents.

Gene profiling approach in the analysis of lymphotoxin and TNF deficiencies.

Mice with combined lymphotoxin-alpha (LTalpha) and tumor necrosis factor (TNF) deficiencies show defects in the structure of peripheral lymphoid organs such as spleen, lymph nodes, and gut-associated lymphoid tissues. To identify genes associated with this defective phenotype in spleen, we applied a gene profiling approach, including subtractive cloning and gene array hybridizations, to mice with combined TNF/LT deficiency. The differentially expressed genes identified by these techniques was then evaluated by Northern blot analysis for splenic expression in knockout mice with single LTalpha or single TNF deficiency. Most of the genes detected in this analysis are directly or indirectly associated with disrupted LT and not TNF signaling.

[An analysis of 3H-tamoxifen binding with the cell plasma membranes of the rat uterus]. / Analiz sviazyvaniia 3H-tamoksifena s plazmaticheskimi membranami kletok matki krys.

The effect of phencarol, ranitidine, propranolol, atropine, and diethylstilbestrol (known as modulators of the tamoxifen-binding sites in plasma membranes) on the 3H-tamoxifen binding to the plasma membrane fraction of white rat uterine cells was studied by determining the amounts of estradiol and H1- and H2-receptors. The interaction of tamoxifen with various receptors of uterine cells may be significant for evaluation of the tumor activity of this compound.

SPLASH (PLA2IID), a novel member of phospholipase A2 family, is associated with lymphotoxin deficiency.

Lymphotoxin (LT) deficient mice have profound defects in the splenic microarchitecture associated with defective expression on certain gene products, including chemokines. By using subtraction cloning of splenic cDNA from wild-type and LT alpha or TNF/LT alpha double deficient mice we isolated a novel murine gene encoding a secretory type phospholipase A2, called SPLASH. The two major alternative transcripts of SPLASH gene are predominantly expressed in lymphoid tissues, such as spleen and lymph nodes. SPLASH maps to the distal part of chromosome 4, to which several cancer-related loci have been also mapped.

TNF and lymphotoxin beta cooperate in the maintenance of secondary lymphoid tissue microarchitecture but not in the development of lymph nodes.

Inactivation of genes encoding members of TNF and TNF receptor families reveal their divergent roles in the formation and function of secondary lymphoid organs. Most lymphotoxin alpha (ltalpha)- and all lymphotoxin beta receptor (ltbetar)-deficient mice are completely devoid of lymph nodes (LNs); however, most lymphotoxin beta (ltbeta)-deficient mice develop mesenteric LNs. Tnf- and tnfrp55-deficient mice develop a complete set of LNs, while ltbeta/tnfrp55 double-deficient mice lack all LNs, demonstrating cooperation between LTbeta and TNFRp55 in LN development. Now we report that ltbeta/tnf double-deficient mice develop the same set of mucosal LNs as do ltbeta-deficient mice, suggesting that ligands other than TNF signal through TNFRp55 during LN development. These LNs retain distinct T and B cells areas; however, they lack follicular dendritic cell networks. Structures resembling germinal centers can be found in the LNs from immunized ltbeta-deficient mice but not in ltbeta/tnf double-deficient mice. Additionally, stromal components of the spleen and LNs appear to be more severely disturbed in ltbeta/tnf double-deficient mice as compared with ltbeta-deficient mice. We conclude that LTbeta and TNF cooperate in the establishment of the correct microarchitecture of lymphoid organs.