Pairwise comparison of isogenic HIV-1 viruses: R5 phenotype replicates more efficiently than X4 phenotype in primary CD4+ T cells expressing physiological levels of CXCR4.

CCR5-using (R5) HIV-1 strains are present during the whole course of the infection in all subjects, whereas CXCR4-using (X4) HIV-1 strains appear only in the late stages of the infection in some subjects. In this study, we tested the hypothesis that this phenomenon might be the result of a replicative advantage of R5 over X4 strains. We compared the infectivity of an R5 and an X4 strain that differ only in their env gene in peripheral blood mononuclear cells.

Peripheral blood T4 cell surface CCR5 density as a marker of activity in rheumatoid arthritis treated with anti-CD20 monoclonal antibody.

The chemokine (C-C motif) receptor CCR5 and its ligand CCL5 play key roles in the intra-articular recruitment of peripheral blood mononuclear cells (PBMC) in rheumatoid arthritis (RA). Therefore, using quantitative cytofluorometry, we followed T4 cell surface CCR5 density in 27 subjects with RA before and after treatment with the anti-CD20 monoclonal antibody rituximab. We observed low T4 cell surface CCR5 densities before treatment, which correlated positively with disease activity, as determined using a disease activity score evaluated on 28 joints (DAS 28), and negatively with CCL5 mRNA concentrations in PBMC, contrasting with a high proportion of intracellular CCR5 molecules, a pattern compatible with ligand-induced CCR5 internalization.

CXCR3 expression on peripheral CD4+ T cells as a predictive marker of response to treatment in chronic hepatitis C.

We monitored in fifty individuals with chronic hepatitis C (CHC) the expression of CCR5 and CXCR3, two chemokine receptors involved in the intra-hepatic recruitment of T cells, at the surface of circulating CD4+ T cells. The percentage of CD4+ T cells expressing CCR5 and/or CXCR3 was increased in patients. The increased percentage of CD4+ CXCR3+ T lymphocytes was linked to serum level of aspartate aminotransferase (AST) and to fibrosis METAVIR score.

The chemokine CCL5 regulates the in vivo cell surface expression of its receptor, CCR5.

The efficiency of CCR5 as an HIV coreceptor is strongly dependent on its level of cell surface expression. Therefore, it is of major importance to identify the factors that regulate cell surface density of CCR5. Among the chemokines that bind to CCR5, and induce its internalization, CCL5 is the most abundant in vivo.

Cell surface CCR5 density determines the intensity of T cell migration towards rheumatoid arthritis synoviocytes.

As we have recently shown that the number of CCR5 molecules at the cell surface determines the efficiency of its function as a chemokine receptor, we tested the hypothesis that cell surface CCR5 density could influence the intensity of T lymphocyte recruitment into the rheumatoid joint. For this purpose, we established two Jurkat cell line-derived clones that differed only by their cell surface CCR5 densities. We studied their chemotaxis towards TNF-alpha-transduced rheumatoid synoviocytes supernatant.

The strength of the chemotactic response to a CCR5 binding chemokine is determined by the level of cell surface CCR5 density.

We have shown that the intensity of expression of the C-C chemokine receptor CCR5 at the single CD4(+) cell level strongly determines the efficiency of its function as a coreceptor for human immunodeficiency virus type 1. By analogy, we examined if the number of CCR5 molecules at the cell surface might determine its chemotactic response to CCR5 ligands. To test this hypothesis, we measured by flow cytometry the migration of primary human T cells towards the CCR5-binding chemokine CCL5 in vitro.

The efficiency of R5 HIV-1 infection is determined by CD4 T-cell surface CCR5 density through G alpha i-protein signalling.

Objective And Design: The intensity of replication of CCR5-using HIV-1 strains is highly dependent on the number of CCR5 molecules on the surface of CD4-positive T cells. The molecular mechanisms responsible for this phenomenon remained so far unclear. As CCR5 co-receptors are coupled to G alpha i and G alpha q proteins, we tested the hypothesis that the activation triggered through these proteins secondary to the interaction between the viral envelope and CCR5 could account for the effect of the level of CCR5 expression on HIV-1 production.

Immunostimulants revisited: focus on the pharmacology of Ribomunyl.

Ribomunyl is an immunostimulant that was developed and commercialized in the 1980s in France and has subsequently been made available in a large number of countries. The formulation is composed of proteoglycans from Klebsiella pneumoniae and of ribosomes from four of the most commonly encountered bacterial strains in recurrent respiratory tract infections. While it is obviously difficult to present a thorough summary of all historical data, here we revisit the mode of action of this immunostimulant and present a perspective in the context of the most recent data and hypotheses on the mechanisms of the antibacterial immune responses.

CXCR4 overexpression during the course of HIV-1 infection correlates with the emergence of X4 strains.

The factors that determine the emergence of X4 isolates in some HIV-1-infected subjects are unknown. As the level of expression of CXCR4 could favor an R5 to X4 switch, quantitative flow cytometry was used to measure CXCR4 density on CD4 T cells in 200 HIV-1-positive adults, and this was compared with CD4 counts, interleukin-7 (IL-7), and RANTES (regulated on activation, normal T expressed and secreted) plasma levels and the R5/X4 virus phenotype. CD4 T-cell surface CXCR4 densities were increased in infected subjects and inversely correlated with CD4 T-cell count (r=-0.

G-protein signaling triggered by R5 human immunodeficiency virus type 1 increases virus replication efficiency in primary T lymphocytes.

The binding of R5 envelope to CCR5 during human immunodeficiency virus type 1 (HIV-1) entry provokes cell activation, which has so far been considered to have no effect on virus replication, since signaling-defective CCR5 molecules have been shown to function normally as HIV-1 coreceptors on transformed cells or mitogen-stimulated T lymphocytes. As the background state of activation of these cells might have biased the results, we performed experiments using the same approach but with nonactivated primary T lymphocytes. We now report that the single R126N mutation in the DRY motif, involved in G-protein coupling, results in a signaling-defective CCR5 coreceptor with a drastically impaired capacity to support HIV-1 infection.

T-Cell surface CCR5 density is not correlated with hepatitis severity in hepatitis C virus/HIV-coinfected individuals: implications for the therapeutic use of CCR5 antagonists.

CCR5 antagonists represent promising anti-HIV agents. Yet, if the CCR5 chemokine receptor plays a positive role in hepatitis C virus (HCV) infection, CCR5 antagonists might be contraindicated in HCV/HIV-coinfected subjects. Therefore, we tested the hypothesis that the level of T-cell surface CCR5 expression, which might determine the intensity of HCV-specific T-cell recruitment into the liver, and thereby the efficiency of the anti-HCV response, could determine HCV disease evolution.

Diminished CD4+ T cell surface CCR5 expression in alcoholic patients.

Aims: The C-C chemokine receptors, particularly the CCR5, appeared to play an important role in T cell-mediated inflammatory reactions. The aim of our study was to assess the impact of chronic alcohol consumption on the in vivo CCR5 expression.

Methods: Fourteen alcoholic men hospitalized for a detoxification programme were prospectively included and compared with 49 age-matched controls.

Feline immunodeficiency virus vectors for efficient transduction of primary human synoviocytes: application to an original model of rheumatoid arthritis.

The potential of gene therapeutics is hindered by the limitations of the delivery systems presently available. Recently, human immunodeficiency virus (HIV) vectors have been developed that allow the efficient and stable transduction of primary nondividing cells in vivo. Because of the safety concerns raised by HIV vectors, we developed a gene delivery system derived from the ungulate lentivirus feline immunodeficiency virus (FIV).

Specific alteration of peripheral cytotoxic cell perforin expression in alcoholic patients: a possible role in alcohol-related diseases.

Background: The association between chronic alcohol consumption and an increasing risk of infectious and neoplastic disease is related to an impairment of cellular immunity. However, studies of the number and activity of lymphocyte subsets show highly variable results. The aim of this study was to assess the expression of perforin, one of the main molecular agents of T and natural killer (NK) cell-mediated cytotoxicity, in alcoholic patients without cirrhosis.

Correlations between clinical, histologic, blood, and skin polymerase chain reaction outcome in patients treated for mycosis fungoides.

Little information is currently available regarding post-treatment outcome of TCR-targeted PCR in skin and/or peripheral blood in patients with Mycosis Fungoides (MF) when a dominant gene rearrangement is present at time of diagnosis. To address this matter, a study evaluating the correlations between post-treatment clinical, histological, blood and skin PCR data was conducted in MF patients. Twenty-seven MF patients with dominant gene rearrangement in skin lesions at time of diagnosis were selected.

Perforin expression in T cells and virological response to PEG-interferon alpha2b in HIV-1 infection.

Objective And Design: Interferon alpha (IFNalpha), which is known to directly inhibit the HIV-1 replicative cycle and to increase the activity of cytotoxic T lymphocytes (CTL), is being tested as an anti-HIV agent. As CTL play a major role in immune defence against HIV, we wanted to further characterize CTL activity and the effect of IFNalpha on it.

Methods: We followed by flow cytometry the intracellular expression of the key mediator of cytotoxicity, perforin, in peripheral blood T cells of patients treated with IFNalpha.

Interferon-alpha restores HIV-induced alteration of natural killer cell perforin expression in vivo.

Objective: The percentage and the activity of natural killer (NK) cells are known to be decreased in HIV-infected patients. However, the mechanisms responsible for this NK deficiency are poorly understood. Because of the role of NK cells in the host defence against microbial infections, this defect contributes to the virus-induced immune deficiency.

Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection.

We have recently reported that the mean number of CCR5 coreceptors at the surface of CD4(+) T cells (CCR5 density) correlates with viral load and disease progression in HIV-1-infected persons. Here, we definitively establish that CCR5 density determines the level of virus production and identify the stages of HIV-1 replicative cycle modulated by this effect. We show, by transducing the CCR5 gene into CCR5(+) cells, that CCR5 overexpression resulted in an HIV-1 overinfectability.

Continuous veno-venous hemofiltration improves hemodynamics in septic shock with acute renal failure without modifying TNFalpha and IL6 plasma concentrations.

Background: Continuous hemofiltration improves hemodynamics in critically ill patients by removing cytokines from the plasma. The mechanism, however, remains to be clarified since recent studies show conflicting findings. The present study was therefore designed to evaluate hemodynamic changes and kinetics of tumor necrosis factor (TNF)alpha, interleukin (IL)1beta and IL6 in patients with septic shock and acute renal failure (ARF) undergoing continuous veno-venous hemofiltration (CWHF), over a 24-hour period.

Response to treatment and disease progression linked to CD4+ T cell surface CC chemokine receptor 5 density in human immunodeficiency virus type 1 vertical infection.

The factors governing interindividual variability in disease progression among children vertically infected with human immunodeficiency virus type 1 (HIV-1) remain unclear. Because it has recently been shown in infected adults that the density of CC chemokine receptor 5 (CCR5) molecules at the surface of nonactivated (human leukocyte antigen [HLA]-DR(-)) CD4+ T cells correlates with disease progression, the same correlation was sought in children. HLA-DR(-)CD4+ T cell surface CCR5 density was constant over time and correlated with the bioclinical stage and with the CD4 cell slope observed before antiretroviral treatment.