In HIV-Infected Immunological Non-Responders, Hepatitis C Virus Eradication Contributes to Incomplete Normalization of Systemic Inflammation Indexes, but Does Not Lead to Rapid CD4+ T-Cell Count Recovery.

In HIV-positive individuals taking antiretroviral therapy, coinfection with hepatitis C virus (HCV) increases systemic inflammation, which interferes with the CD4+ T-cells regeneration. This study evaluated the effect of HCV eradication on systemic inflammation and CD4+ T-cell regeneration in patients who gave poor response to antiretroviral therapy, the so-called "immunological non-responders" (INRs). HIV-infected patients who received a course of direct-acting antivirals for treating hepatitis C were examined. The control groups included HIV/HCV-coinfected INRs and relatively healthy volunteers. It was established for the first time that HCV eradication is not accompanied by a complete suppression of systemic inflammation, but improves the T-cell pool composition: in INRs, the blood CD4+/CD8+ T-lymphocyte ratio increases and approaches those of healthy individuals. Apparently, in INRs treated for hepatitis C, the immune system recovery takes time and may be incomplete.

Metabolic Features of Activated Memory CD4+ T-Cells Derived from HIV-Infected Immunological Non-responders to Highly Active Antiretroviral Therapy.

Immunological non-responders (INR) are HIV-infected subjects that fail to restore CD4+ T-cell counts despite undetectable HIV viral load, which is controlled by highly active antiretroviral therapy (HAART). In INR, impaired immune restoration is linked to low-productive proliferation of memory CD4+ T-lymphocytes. Taking into account that T-cell ability to divide depends on the activity of metabolic pathways, we aimed to determine rates of mitochondrial respiration and glycolysis in memory CD4+ T-cells of INR. Two groups of HIV-infected HAART-treated patients were studied: immunological non-responders and subjects with an adequate immunological response to therapy (immunological responders - IR). Control (C) group comprised uninfected volunteers. In both groups of HIV-infected patients glycolytic activity of memory CD4+ T-cells was lower than that in C. Mitochondrial respiration rate in memory CD4+ T-cells derived from IR was comparable to that of C at basal state, however, after stimulation IR failed to reach the values of uninfected subjects. INR had the lowest mitochondrial respiration rate both at basal state and after stimulation. Taken together, the data presented herein demonstrate that low regenerative potential of memory CD4+ T-cells derived from INR might be linked to diminished lymphocytes' metabolic activity.

Changes in the Regulatory T-Lymphocyte Counts in HIV-Infected Patients with a Discordant Response to Antiretroviral Therapy.

We examined HIV-infected patients with different efficacies of immune system restoration during antiretroviral therapy. The study showed that against the background of low CD4+ T cell counts, subjects with a discordant immunologic response (patients with <350 CD4+ T cells per µL of blood after more than two years of treatment) develop a regulatory CD4+ T cell (Treg) deficiency. Furthermore, in these patients, the immunodeficiency is accompanied by an increase in the Treg frequency. Accumulation of regulatory T lymphocytes in the blood of HIV­infected subjects with discordant response to the treatment indicates a high viability of this T cell subset.

CD8+ T cell expansion in HIV/HCV coinfection is associated with systemic inflammation.

High prevalence of non-AIDS-defining illnesses in treated HIV-infected patients is associated with increased peripheral CD8+ T cell counts. Hepatitis C virus (HCV) coinfection is an additional risk factor for the development of non-AIDS events. We found that, in HIV/HCV coinfection, the increased proportion of CD8+ T lymphocytes is due to the effector memory and terminal effector T cells gain. Moreover, in these patients, the accumulation of highly differentiated forms of CD8+ T lymphocytes was associated with increased concentrations of inflammatory indices.

HCV coinfection of the HIV-infected patients with discordant CD4+ T-cell response to antiretroviral therapy leads to intense systemic inflammation.

The level of proinflammatory markers was assessed in HIV-infected patients that were coinfected with hepatitis C virus (HCV) and had failed to restore the CD4+ T cell counts (immunological nonresponders, INR) during the antiretroviral therapy (ART). Among four patient groups (HIV+HCV- and HIV+HCV+ subjects with the concordant response to ART; HIV+HCV- and HIV+HCV+ subjects that were INR), the greatest systemic inflammation was in the latter group. The maximum difference was between the subjects HIV+HCV-INR and HIV+HCV+ INR: the blood of coinfected patients contained significantly higher concentrations of the IP-10, sCD163, sTNF-RI, and sTNF-RII and of bacterial lipopolysaccharide. Systemic inflammation in HIV/HCV coinfected patients with the discordant response to ART is probably caused by a breach of hepatic barrier for the intestine products.

Systemic inflammation and liver damage in HIV/hepatitis C virus coinfection.

OBJECTIVES: Chronic hepatitis C virus (HCV) and HIV viral infections are characterized by systemic inflammation. Yet the relative levels, drivers and correlates of inflammation in these settings are not well defined. METHODS: Seventy-nine HIV-infected patients who had been receiving antiretroviral therapy (ART) for more than 2 years and who had suppressed plasma HIV levels (< 50 HIV-1 RNA copies/mL) were included in the study. Two patient groups, HCV-positive/HIV-positive and HCV-negative/HIV-positive, and a control group comprised of healthy volunteers (n = 20) were examined. Markers of systemic inflammation [interleukin (IL)-6, interferon gamma-induced protein (IP)-10, soluble tumour necrosis factor receptor-I (sTNF-RI) and sTNF-RII], monocyte/macrophage activation [soluble CD163 (sCD163), soluble CD14 and neopterin], intestinal epithelial barrier loss [intestinal fatty acid binding protein (I-FABP) and lipopolysaccharide (LPS)] and coagulation (d-dimers) were analysed. CD4 naïve T cells and CD4 recent thymic emigrants (RTEs) were enumerated. RESULTS: Plasma levels of IP-10, neopterin and sCD163 were higher in HCV/HIV coinfection than in HIV monoinfection and were positively correlated with indices of hepatic damage [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the AST to platelet ratio index (APRI)]. Levels of I-FABP were comparably increased in HIV monoinfection and HIV/HCV coinfection but LPS concentrations were highest in HCV/HIV coinfection, suggesting impaired hepatic clearance of LPS. Plasma HCV levels were not related to any inflammatory indices except sCD163. In coinfected subjects, a previously recognized relationship of CD4 naïve T-cell and RTE counts to hepatocellular injury was defined more mechanistically by an inverse relationship to sCD163. CONCLUSIONS: Hepatocellular injury in HCV/HIV coinfection is linked to elevated levels of certain inflammatory cytokines and an apparent failure to clear systemically translocated microbial products. A related decrease in CD4 naïve T cells and RTEs also merits further exploration.

Effect of Hepatitis C Virus Coinfection on the Content of CD4(+) and CD8(+) T Cell Subpopulations in HIV-Infected Patients Receiving Antiretroviral Therapy.

We studied the effect of hepatitis C virus coinfection on T cell subpopulations in HIV-infected patients receiving antiretroviral therapy. Coinfection with hepatitis C virus was followed by a decrease in the number of naive CD4(+) T cells and an increase in the count of central CD8(+) memory T cells in these patients. Hepatitis C virus had no effect on the number of CD4(+) memory T cells (main target for HIV). This can explain the absence of strong negative effect of hepatitis C virus on the course of HIV infection.

Immune complexes that contain HIV antigens activate peripheral blood T cells.

Uninfected donor T cells were treated in vitro by model immune complexes that contained either HIV or hepatitis C virus (HCV) antigens. Unlike HCV antigen-containing complexes, the immune complexes that contained HIV antigens have been shown to activate peripheral blood T cells of uninfected donors under in vitro conditions. Both the antiviral antibodies and HIV antigen were involved in the activation process. The unique properties of the immune complexes formed by HIV antigens and antiviral antibodies are believed to result from the virus-specific antibody properties and molecular conformation of the antigen-antibody complex.

[Causes of T lymphocyte activation in HIV-infected patients coinfected with hepatitis C virus]. / Prichiny aktivatsii T-limfotsitov u VICh-infitsiro-vannykh patsientov, koinfitsirovannykh virusom gepatita C.

AIM: To establish the causes of T lymphocyte activation in human immunodeficiency virus (HIV)-infected patients coinfected with hepatitis C (HCV) who are adherent to their antiretroviral therapy regimen and interferon untreated. SUBJECTS AND METHODS: Examinations were made in 62 people who were HIV+HCV-positive (n=21), HIV+HCV-negative (n=21), and noninfected volunteers (n=20). The activation (CD38+HLA-DR+) and proliferation (Ki-67+) of CD4+ and CD8+ T lymphocytes were estimated. The blood concentration of intestinal fatty acid-binding protein (I-FABP) was determined. RESULTS: The proportion of activated cells among the CD4+ T lymphocytes was equal in the HIV+HCV-positive and HIV+HCV-negative groups. But these indicators were statistically significantly higher than those in the controls (HIV- HCV-). CD8+ T cell activation was greater in the HIV/HCV-coinfected patients than that in the other groups and that was higher in the HIV monoinfected than in the noninfected. The blood I-FABP concentrations were elevated in the HIV+HCV-positive and HIV+HCV groups compared with those in the HIV-HCV-negative group, but these did not differ among themselves. In the HIV+HCV-negative patients, CD4+ and CD8+ T cell activation directly and statistically significantly correlated with blood I-FABP levels. In the HIV+HCV-positive group, this correlation remained only for CD4+ T lymphocytes. CD8+ T cell activation in HIV/HCV-coinfected patients was unrelated to I-FABP concentrations. CONCLUSION: The increased activation of CD4+ and CD8+ T lymphocytes in HIV monoinfection was found to be associated with intestinal epithelial destruction and unrelated to cell division processes. In HIV/HCV coinfection, the activated state of CD4+ T cells is determined by both the level of proliferative processes and impairment of the intestinal barrier and that of CD8+ T cells is only by proliferation.

[SYSTEMIC INFLAMMATION AND COMPROMISED INTESTINAL BARRIER DURING SUCCESSFUL TREATMENT OF HIV INFECTION].

UNLABELLED: The relationship between immunity disorders, destruction of intestinal barrier and development of systemic inflammation during antiviral therapy in patients with HIV infection is a topical issue in terms of suppression of virus replication and reduction of its role in the pathological process. STUDY OBJECT: Blood of HIV-infected patients given antiretroviral therapy (n = 21) and non-infected volunteers (n = 20). METHODS: Identification of cells among CD4⁺ and CD8⁺ T-lymphocytes expressing markers of activation (CD38, HLA-DR), depletion (PD-1), and interleukin (IL) 7 receptor (CD127); measurement of blood levels of IL-6, neopterin, soluble CD14 (sCD14), intestinal fatty acid-binding peptide (I-FABP), and bacterial lipopolysaccharide. Correlation analysis of the dependence between cell immunity and systemic inflammation was performed. RESULTS: HIV-infected patients had more activated CD4⁺ and CD8⁺ T-lymphocytes and CD4⁺ T-cells expressing PD-1 marker than non-infected subjects but less CD4⁺ and CD8+ T-lymphocytes expressing CD127. Blood IL-6, neopterin, soluble CD14, I-FABP and bacterial lipopolysaccharide levels in the former were higher than in the latter HIV-infected patients showed significant correlation of cell immunity parameters with blood neopterin and FABP levels. CONCLUSION: The process of activation, depletion, and regeneration of T-lymphocytes in. HIV infection are related to the destruction of intestinal barrier and systemic macrophage activation.

Characteristics of Circulating Immune Complexes in HIV-Infected Patients with Different Viral Load.

Serum concentration of antiviral antibodies was measured in HIV-infected patients with different viral load. It was found that higher concentrations of HIV-antigens correspond to higher titer of antiviral antibodies. Circulating immune complexes were isolated from patients' serum to estimate their size and immunoglobulin composition. High levels of small IgG- and IgM-containing complexes were identified in HIV-infected patients. In patients receiving antiretroviral treatment, the content of these complexes was significantly lower than in patients with high HIV load. This attests to positive role of specific therapy in preventing immune complex-associated pathology in HIV patients.

Discordant response of CD4(+) T cells to antiretroviral therapy in HIV-infected patients coinfected with hepatitis C virus is accompanied by increased liver damage.

A study of HIV-infected patients coinfected with hepatitis C virus and receiving antiretroviral therapy (ART) but not treated with interferon was performed. Patients were divided into two groups-with standard and inefficient recovery of CD4(+) T cells. It was found that patients with discordant response of CD4(+) T cells to ART showed heavier destructive processes in the liver than the successfully recovered subjects. They had increased levels of ALT and AST. In these patients, the risk of development of liver cirrhosis is greater.

[The evaluation of thymus function on the basis of circular DNA estimation technique].

The production of T-lymphocytes by thymus is an important indicator of functioning of immune system. The article discusses one of the actual techniques of evaluation of productive function of thymus i.e. qualitative analysis of intracellular circular DNA of T-cells of peripheral blood (TREC). The stages of adaptation of technique on the basis of nationally produced reagents and instruments. To assure the implementation of qualitative polymerase chain reaction a pair of primers with specific sequence of marker of recent thymus emigrants was selected. The optimization of temperature regimen of amplification was made. To ensure the transition to the qualitative analysis on the basis of polymerase chain reaction technic in real-time a fluorescent probe complementary to amplicone nucleotide sequence was developed. The following analytic characteristics of technique were established: sensitivity 4 ng/ml, reproducibility 1.8%. The valid discrepancy of TREC concentrations in patients of different age groups is demonstrated.

Molecular bases of immune complex pathology.

The binding of antigens with antibodies forms immune complexes in the body. Usually these complexes are eliminated by the system of mononuclear phagocytes without development of pathological changes. This review highlights principal mechanisms responsible for safe removal of immune complexes in primates and humans. Special attention is given to diseases known as "immune complex diseases", when antigen-antibody complexes induce inflammatory reactions. The review considers key experimental works that significantly contributed to current knowledge of etiology and pathogenesis of type III hypersensitivity. Some factors of the development of immune complex syndrome such as level of humoral immune response to antigen, isotype and affinity of forming antibodies, the amount of immune complexes, and the consequences of their interaction with the complement system and Fc-receptors are analyzed based on the molecular mechanisms involved. The review contains a retrospective analysis of the most significant scientific achievements in immune complex pathology investigation within the last 100 years.

[Steroid hormones: their physiological role and diagnostic value during pregnancy]. / Steroidnye gormony: fiziologicheskaia rol' i diagnosticheskoe znachenie v period beremennosti.

Steroid hormones play a key role in the beginning, development and termination of gestation. This reveiw is devoted for physiological effects of estrogens, progesterone, cortisole, ACTH, CRH in various pregnancy events: implantation, fetus development, maternal adaptation and birth initiation. Priority is fixed for estrogens--steroids that vastly increase maternal circulating blood value, induce progesterone action on uterus, regulate fetal "hypothalamic-pituitary-adrenocortical" axis, control free cortisole level in feminine blood. Diagnostic criterions of steroid hormone determination durijng pregnancy are presented. To day unconjugated estriol is the only steroid hormone that implicated in total pregnancy screening programs. Its concentration reduction has been noted in pregnancies with Dawn syndrome, some child enzyme defetcs, intrauterine growth retardation and fetal death incidents.

[Use of a mathematical model to establish normal serum parameters characterizing the function of the fetoplacental complex]. / Ispol'zovanie matematicheskogo modelirovaniia dlia polucheniia znachenii normy syvorotochnykh pokazatelei, kharakterizuiushchikh funktsiiu feto-platsentarnogo kompleksa.

Based on the author, data on the content of alpha-fetoprotein, trophoblastic beta-1-glycoprotein, and nonconjugated estriol in the blood serum of 278 somatically healthy women in various periods of normal gestation, the author proposes an approach to the definition of normal range of values. Using mathematical simulation methods, the values of normal concentrations of the fetoplacental complex products were calculated for every week of gestation, this permitting a different representation of laboratory findings and a dynamic follow-up of the course of gestation.