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Find video protocols related to scientific articles indexed in Pubmed.
Plasmacytoid dendritic cells mediate synergistic effects of HIV and lipopolysaccharide on CD27+ IgD- memory B cell apoptosis.
J. Virol.
PUBLISHED: 07-23-2014
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The effects of heightened microbial translocation on B cells during HIV infection are unknown. We examined the in vitro effects of HIV and lipopolysaccharide (LPS) on apoptosis of CD27+ IgD- memory B (mB) cells from healthy controls. In vivo analysis was conducted on a cohort of 82 HIV+ donors and 60 healthy controls. In vitro exposure of peripheral blood mononuclear cells (PBMCs) to LPS and HIV led to mB cell death via the Fas/Fas ligand (FasL) pathway. Plasmacytoid dendritic cells (pDCs) produced FasL in response to HIV via binding to CD4 and chemokine coreceptors. HIV and LPS increased Fas expression on mB cells in PBMCs, which was dependent on the presence of pDCs and monocytes. Furthermore, mB cells purified from PBMCs and pretreated with both HIV and LPS were more sensitive to apoptosis when cocultured with HIV-treated pDCs. Blocking the interferon receptor (IFNR) prevented HIV-stimulated FasL production in pDCs, HIV-plus-LPS-induced Fas expression, and apoptosis of mB cells. In vivo or ex vivo, HIV+ donors have higher levels of plasma LPS, Fas expression on mB cells, and mB cell apoptosis than controls. Correspondingly, in HIV+ donors, but not in controls, a positive correlation was found between plasma FasL and HIV RNA levels and between Fas expression on mB cells and plasma LPS levels. This work reveals a novel mechanism of mB cell apoptosis mediated by LPS and HIV through the Fas/FasL pathway, with key involvement of pDCs and type I IFN, suggesting a role for microbial translocation in HIV pathogenesis.
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Rosuvastatin preserves renal function and lowers cystatin C in HIV-infected subjects on antiretroviral therapy: the SATURN-HIV trial.
Clin. Infect. Dis.
PUBLISHED: 07-11-2014
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In chronic human immunodeficiency virus (HIV) infection, plasma cystatin C may be influenced by factors other than glomerular filtration rate such as inflammation. Statins may improve cystatin C by improving glomerular function or by decreasing inflammation.
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Markers of coagulation and inflammation often remain elevated in ART-treated HIV-infected patients.
Curr Opin HIV AIDS
PUBLISHED: 07-08-2014
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Current antiretroviral therapies have dramatically changed the disease course of HIV infection. Although antiretroviral therapy is effective at decreasing viral replication and preserving CD4 T-cell numbers, low-level immune activation and inflammation persist in virally suppressed HIV-infected patients. This chronic immune activation/inflammation may contribute to an increased risk for venous and arterial thrombosis.
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Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals.
PLoS Pathog.
PUBLISHED: 06-01-2014
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Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation--a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that persistent intestinal epithelial dysregulation involving a reduction in TJ expression is a mechanism driving increases in colonic permeability and microbial translocation in the ART-treated HIV-infected patient, and a possible immunopathogenic factor for non-AIDS related complications.
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Sevelamer Does Not Decrease Lipopolysaccharide or Soluble CD14 Levels But Decreases Soluble Tissue Factor, Low-Density Lipoprotein (LDL) Cholesterol, and Oxidized LDL Cholesterol Levels in Individuals With Untreated HIV Infection.
J. Infect. Dis.
PUBLISHED: 05-26-2014
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Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits.
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Coagulation and morbidity in treated HIV infection.
Thromb. Res.
PUBLISHED: 04-25-2014
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HIV infected patients are at increased risk for venous and arterial thromboembolic events. Multiple markers related to inflammation (IL-6, TNFrI, C-reative protein) and coagulation (tissue factor expression, FVIII, thrombin, fibrinogen and D-dimer levels) are increased in HIV infection, and several are predictive of thrombotic risk and mortality in HIV disease. The mechanisms behind the risk for abnormal coagulation in HIV infection have not been fully elucidated, but may be related to a chronic immune activation and inflammatory state in both untreated and treated HIV infection. The contribution of traditional risk factors, including smoking and dyslipidemia, overly represented in HIV infected patients, must also be considered when assessing thrombotic risk in this setting. Currently, several interventional studies are aimed at reducing inflammation and cardiovascular risk in HIV disease and may provide insights into the determinants of clotting events in HIV infected patients.
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Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection.
J. Infect. Dis.
PUBLISHED: 04-21-2014
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While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear.
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Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection.
AIDS
PUBLISHED: 04-03-2014
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To use multimodality imaging to explore the relationship of biomarkers of inflammation, T-cell activation and monocyte activation with coronary calcification and subclinical vascular disease in a population of HIV-infected patients on antiretroviral therapy (ART).
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Inflammatory cytokines drive CD4+ T-cell cycling and impaired responsiveness to interleukin 7: implications for immune failure in HIV disease.
J. Infect. Dis.
PUBLISHED: 02-28-2014
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Systemic inflammation has been linked to a failure to normalize CD4(+) T-cell numbers in treated human immunodeficiency virus (HIV) infection. Although inflammatory cytokines such as interleukin 6 (IL-6) are predictors of disease progression in treated HIV infection, it is not clear how or whether inflammatory mediators contribute to immune restoration failure.
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Cycling memory CD4+ T cells in HIV disease have a diverse T cell receptor repertoire and a phenotype consistent with bystander activation.
J. Virol.
PUBLISHED: 02-12-2014
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The mechanisms of increased memory CD4+ T cell cycling in HIV disease are incompletely understood but have been linked to antigen stimulation, homeostatic signals, or exposure to microbial products and the inflammatory cytokines that they induce. We examined the phenotype and V? family distribution in cycling memory CD4+ T cells among 52 healthy and 59 HIV-positive (HIV+) donors. Cycling memory CD4+ T cells were proportionally more frequent in subjects with HIV infection than in controls, more often expressed CD38 and PD-1, and less frequently expressed OX40 and intracellular CD40L. OX40 expression on memory CD4+ T cells was induced in vitro by anti-CD3, interleukin-2 (IL-2), IL-7, or IL-15 but not by Toll-like receptor ligands. In HIV+ donors, memory CD4+ T cell cycling was directly related to plasma lipopolysaccharide (LPS) levels, to plasma HIV RNA levels, and to memory CD8+ T cell cycling and was inversely related to peripheral blood CD4+ T cell counts but not to the levels of IL-2, IL-7, or IL-15, while in HIV-negative donors, memory CD4+ T cell cycling was related to IL-7 levels and negatively related to the plasma levels of LPS. In both controls and HIV+ donors, cycling memory CD4+ T cells had a broad distribution of V? families comparable to that of noncycling cells. Increased memory CD4+ T cell cycling in HIV disease is reflective of generalized immune activation and not driven primarily by cognate peptide stimulation or exposure to common gamma-chain cytokines. This cycling may be a consequence of exposure to microbial products, to plasma viremia, or, otherwise, to proinflammatory cytokines.
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Effect of 24 weeks of statin therapy on systemic and vascular inflammation in HIV-infected subjects receiving antiretroviral therapy.
J. Infect. Dis.
PUBLISHED: 01-09-2014
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Human immunodeficiency virus (HIV)-infected individuals are at increased risk of cardiovascular disease (CVD) due in part to inflammation. Statins decrease inflammation in the general population, but their effect during HIV infection is largely unknown.
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Alterations in regulatory T cell subpopulations seen in preterm infants.
PLoS ONE
PUBLISHED: 01-01-2014
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Regulatory T cells are a population of CD4+ T cells that play a critical role in peripheral tolerance and control of immune responses to pathogens. The purpose of this study was to measure the percentages of two different regulatory T cells subpopulations, identified by the presence or absence of CD31 (Recent thymic emigrants and peripherally induced naïve regulatory T cells), in term and preterm infant cord blood. We report the association of prenatal factors, intrauterine exposure to lipopolysaccharide and inflammation and the percentages of these regulatory T cell subpopulations in term and preterm infants. Cord blood samples were collected from both term and preterm infants and mononuclear cells isolated over a Ficoll-Hypaque cushion. Cells were then stained with fluorochrome-labeled antibodies to characterize regulatory T cell populations and analyzed with multi-color flow cytometry. Cord blood plasma C-reactive protein, and lipopolysaccharide were also measured. Placental pathology was also examined. We report a gestational age-dependent difference in the percentage of total regulatory T cells, in which preterm infants of lower gestational ages have an increased percentage of regulatory T cells. We report the presence of two populations of regulatory T cells (CD31+ and CD31-) in cord blood of term and preterm infants and their association with different maternal and fetal characteristics. Factors associated with differences in the percentage of CD31- Tregs included the use of prenatal antibiotics, steroids and magnesium sulfate. In addition, the percentage of CD31- Tregs was significantly higher in cord blood of preterm pregnancies associated with inflammation and prenatal lipopolysaccharide exposure. The peripheral Treg pool of preterm infants could be altered by prenatal exposure to inflammation and chorioamnionitis; however, the clinical implications of this finding are not yet understood.
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Rosuvastatin Treatment Reduces Markers of Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy.
Clin. Infect. Dis.
PUBLISHED: 11-18-2013
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Background.?Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects that are independent of their lipid-lowering properties. Despite suppressive antiretroviral therapy (ART), elevated levels of immune activation and inflammation often persist. Methods.?The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial is a randomized, double-blind, placebo-controlled study, designed to investigate the effects of rosuvastatin (10 mg/daily) on markers of cardiovascular disease risk in ART-treated human immunodeficiency virus (HIV)-infected subjects. A preplanned analysis was to assess changes in markers of immune activation at week 24. Subjects with low-density lipoprotein cholesterol <130 mg/dL and heightened immune activation (%CD8(+)CD38(+)HLA-DR(+) ?19%, or plasma high-sensitivity C-reactive protein ?2 mg/L) were randomized to receive rosuvastatin or placebo. We measured plasma (soluble CD14 and CD163) and cellular markers of monocyte activation (proportions of monocyte subsets and tissue factor expression) and T-cell activation (expression of CD38, HLA-DR, and PD1). Results.?After 24 weeks of rosuvastatin, we found significant decreases in plasma levels of soluble CD14 (-13.4% vs 1.2%, P = .002) and in proportions of tissue factor-positive patrolling (CD14(Dim)CD16(+)) monocytes (-38.8% vs -11.9%, P = .04) in rosuvastatin-treated vs placebo-treated subjects. These findings were independent of the lipid-lowering effect and the use of protease inhibitors. Rosuvastatin did not lead to any changes in levels of T-cell activation. Conclusions.?Rosuvastatin treatment effectively lowered markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. Clinical Trials Registration.?NCT01218802.
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Residual immune dysregulation syndrome in treated HIV infection.
Adv. Immunol.
PUBLISHED: 07-27-2013
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Antiretroviral therapy has revolutionized the course of HIV infection, improving immune function and decreasing dramatically the mortality and morbidity due to the opportunistic complications of the disease. Nonetheless, even with sustained suppression of HIV replication, many HIV-infected persons experience a syndrome characterized by increased T cell activation and evidence of heightened inflammation and coagulation. This residual immune dysregulation syndrome or RIDS is more common in persons who fail to increase circulating CD4+ T cells to normal levels and in several epidemiologic studies it has been associated with increased morbidity and mortality. These morbid and fatal events are not the typical opportunistic infections and malignancies seen in the early AIDS era but rather comprise a spectrum of cardiovascular events, liver disease, metabolic disorders, kidney disease, bone disease, and a spectrum of malignant complications distinguishable from the opportunistic malignancies that characterized the earlier days of the AIDS epidemic. While immune activation, inflammation, and coagulopathy are characteristic of untreated HIV infection and improve with drug-induced control of HIV replication, the drivers of RIDS in treated HIV infection are incompletely understood. And while inflammation, immune activation, and coagulopathy are more common in treated persons who fail to restore circulating CD4+ T cells, it is not entirely clear how these two phenomena are linked.
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Human beta defensin-3 induces chemokines from monocytes and macrophages: Diminished activity in cells from HIV-infected persons.
Immunology
PUBLISHED: 06-06-2013
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Human beta defensin-3 (hBD-3) is an antimicrobial peptide with diverse functionality. We investigated the capacity of hBD-3 and for comparison, Pam3CSK4 and LL-37, to induce co-stimulatory molecules and chemokine expression in monocytes. These stimuli differentially induced CD80 and CD86 on the surface of monocytes and each stimulant induced a variety of chemokines including MCP-1, Gro-alpha, MDC and Mip1beta, while only hBD-3 and Pam3CSK4 significantly induced the angiogenesis factor, Vascular endothelial growth factor. HBD-3 induced similar chemokines in monocyte-derived macrophages and additionally induced expression of RANTES in these cells. Comparison of monocytes from HIV+ and HIV- donors indicated that monocytes from HIV+ donors were more likely to spontaneously express certain chemokines (Mip1alpha, Mip1beta and MCP-1) and less able to increase expression of other molecules in response to hBD-3 (MDC, Gro-alpha and VEGF). Chemokine receptor expression (CCR5, CCR2 and CXCR2) was relatively normal in monocytes from HIV+ donors compared to cells from HIV- donors with the exception of diminished expression of the receptor for MDC, CCR4, which was reduced in the patrolling monocyte subset (CD14+CD16++) of HIV+ donors. These observations implicate chemokine induction by hBD-3 as a potentially important mechanism for orchestrating cell migration into inflamed tissues. Alterations in chemokine production or their receptors in monocytes of HIV-infected persons could influence cell migration and modify the effects of hBD-3 at sites of inflammation. This article is protected by copyright. All rights reserved.
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Perivascular fat, inflammation, and cardiovascular risk in HIV-infected patients on antiretroviral therapy.
Int. J. Cardiol.
PUBLISHED: 05-14-2013
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HIV-infection is characterized by chronic immune activation that persists despite effective antiretroviral therapy (ART) and is associated with elevated cardiovascular risk. Whether specific perivascular fat depots are associated with inflammation in HIV is unknown.
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The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial.
Blood
PUBLISHED: 04-15-2013
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The CCR5 inhibitor maraviroc has been hypothesized to decrease T-cell activation in HIV-infected individuals, but its independent immunologic effects have not been established in a placebo-controlled trial. We randomized 45 HIV-infected subjects with CD4 counts <350 cells per mm(3) and plasma HIV RNA levels <48 copies per mL on antiretroviral therapy (ART) to add maraviroc vs placebo to their regimen for 24 weeks followed by 12 weeks on ART alone. Compared with placebo-treated subjects, maraviroc-treated subjects unexpectedly experienced a greater median increase in % CD38+HLA-DR+ peripheral blood CD8+ T cells at week 24 (+2.2% vs -0.7%, P = .014), and less of a decline in activated CD4+ T cells (P < .001). The % CD38+HLA-DR+ CD4+ and CD8+ T cells increased nearly twofold in rectal tissue (both P < .001), and plasma CC chemokine receptor type 5 (CCR5) ligand (macrophage-inflammatory protein 1?) levels increased 2.4-fold during maraviroc intensification (P < .001). During maraviroc intensification, plasma lipopolysaccharide declined, whereas sCD14 levels and neutrophils tended to increase in blood and rectal tissue. Although the mechanisms explaining these findings remain unclear, CCR5 ligand-mediated activation of T cells, macrophages, and neutrophils via alternative chemokine receptors should be explored. These results may have relevance for trials of maraviroc for HIV preexposure prophylaxis and graft-versus-host disease. This trial was registered at www.clinicaltrials.gov as #NCT00735072.
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Plasma proteome analysis reveals overlapping, yet distinct mechanisms of immune activation in chronic HCV and HIV infections.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 03-20-2013
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HIV infection contributes to accelerated rates of progression of liver fibrosis during hepatitis C virus (HCV) infection, and HCV liver disease contributes to mortality during HIV infection. Although mechanisms underlying these interactions are not well known, soluble and cellular markers of immune activation associate with disease progression during both infections.
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Circulating CD4(+) and CD8(+) T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation.
Immunology
PUBLISHED: 03-19-2013
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Inflammatory bowel disease (IBD) is characterized by damage to the gut mucosa and systemic inflammation. We sought to evaluate the role of chronic inflammation on circulating T-cell activation in human subjects with Crohns disease and ulcerative colitis. We studied 54 patients with IBD and 28 healthy controls. T-cell activation and cycling were assessed in whole blood samples by flow cytometry. Levels of lipopolysaccharide (LPS) were measured in serum by Limulus amoebocyte lysate assay, and plasma levels of inflammatory markers and LPS-binding proteins were measured by ELISA. The proportions of circulating CD4(+) and CD8(+) T lymphocytes in cycle (Ki67(+) ) are increased in patients with IBD compared with these proportions in controls. CD8(+) T cells from patients with IBD are also enriched for cells that expressed CD38 and HLA-DR, and proportions of these cells are related to plasma levels of interleukin-6 and C-reactive protein in these patients. Intracellular interleukin-2 and interferon-? levels were elevated in resting and polyclonally activated CD4(+) and CD8(+) T cells in patients with IBD when compared with levels from healthy controls. Surprisingly, we did not find increased levels of LPS in the serum of patients with IBD. We did, however, find a signature of recent microbial translocation, as levels of LPS-binding protein are increased in the plasma of patients with IBD compared with plasma levels in healthy controls; LPS-binding protein levels are also directly related to proportions of CD38 HLA-DR-expressing CD4(+) and CD8(+) T cells. Local damage to the gastrointestinal tract in IBD may result in systemic inflammation and T-cell activation.
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Systemic immune activation and microbial translocation in dual HIV/tuberculosis-infected subjects.
J. Infect. Dis.
PUBLISHED: 03-11-2013
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Systemic immune activation is a strong predictor of progression of human immunodeficiency virus type 1 (HIV-1) disease and a prominent feature of infection with Mycobacterium tuberculosis.
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Decreased IL-7 responsiveness is related to oxidative stress in HIV disease.
PLoS ONE
PUBLISHED: 02-06-2013
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HIV disease results in decreased IL-7 receptor expression and IL-7 responsiveness in T cells. To explore mechanisms of these deficiencies, we compared CD127 expression and IL-7 induction of P-STAT5 in T cells from HIV-infected persons with serum concentrations of cytokines (IL-7, IL-6 and IL-15), markers of microbial translocation (sCD14 and LPS), and with an indicator of oxidative stress (malondialdehyde (MDA) adducts). CD127 expression was directly related to IL-7 responsiveness in most CD8+ T cell subsets but not in CD4+ T cells from HIV-infected persons. MDA adducts were increased in serum of HIV-infected patients and were inversely related to IL-7 responsiveness in CD8+ T cells and in central memory CD4+ T cells. Incubation of T cells from healthy controls with hydrogen peroxide resulted in impairments in IL-7 induction of P-STAT5. These findings suggest that oxidative stress that is characteristic of HIV disease could contribute to impairments in IL-7 responsiveness and disrupt T cell homeostasis.
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Lipopolysaccharide and soluble CD14 in cord blood plasma are associated with prematurity and chorioamnionitis.
Pediatr. Res.
PUBLISHED: 02-01-2013
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Background:Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, causes preterm birth in animals and has been implicated as a factor triggering preterm labor and systemic complications in humans. Little is known regarding LPS in the cord blood (CB) of term and preterm infants and its association with maternal and fetal characteristics.Methods:CB was obtained from term (n = 15) and preterm infants (n = 76) after delivery. Plasma levels of LPS, C-reactive protein (CRP), and soluble CD14 (sCD14) were measured using commercially available kits (limulus amebocyte lysate and enzyme-linked immunosorbent assay). Four linear regression models were created in order to identify independent variables that predict plasma LPS levels.Results:The analyte levels were significantly higher in preterm vs. term infant CB: LPS (24.48 vs. 1 pg/ml; P = 0.0009), CRP (87.9 vs. 47?ng/ml; P = 0.01), and sCD14 (0.32 vs.0.35 µg/ml; P = 0.013). There was a (significant) positive correlation between CB LPS levels and gestational age, birth weight, CRP levels, sCD14 levels, and association with both clinical and histological chorioamnionitis.Conclusion:Our data suggest that LPS is associated with preterm labor and inflammation (CRP elevation and chorioamnionitis). These findings may be relevant to the understanding of the role of LPS in prematurity and its role in preterm morbidities.Pediatric Research (2013); doi:10.1038/pr.2013.182.
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Probiotic/prebiotic supplementation of antiretrovirals improves gastrointestinal immunity in SIV-infected macaques.
J. Clin. Invest.
PUBLISHED: 01-16-2013
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HIV infection results in gastrointestinal (GI) tract damage, microbial translocation, and immune activation, which are not completely ameliorated with suppression of viremia by antiretroviral (ARV) therapy. Furthermore, increased morbidity and mortality of ARV-treated HIV-infected individuals is associated with these dysfunctions. Thus, to enhance GI tract physiology, we treated SIV-infected pigtail macaques with ARVs, probiotics, and prebiotics or with ARVs alone. This synbiotic treatment resulted in increased frequency and functionality of GI tract APCs, enhanced reconstitution and functionality of CD4+ T cells, and reduced fibrosis of lymphoid follicles in the colon. Thus, ARV synbiotic supplementation in HIV-infected individuals may improve GI tract immunity and thereby mitigate inflammatory sequelae, ultimately improving prognosis.
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Interferon-? is the primary plasma type-I IFN in HIV-1 infection and correlates with immune activation and disease markers.
PLoS ONE
PUBLISHED: 01-10-2013
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Type-I interferon (IFN-I) has been increasingly implicated in HIV-1 pathogenesis. Various studies have shown elevated IFN-I and an IFN-I-induced gene and protein expression signature in HIV-1 infection, yet the elevated IFN-I species has not been conclusively identified, its source remains obscure and its role in driving HIV-1 pathogenesis is controversial. We assessed IFN-I species in plasma by ELISAs and bioassay, and we investigated potential sources of IFN-I in blood and lymph node tissue by qRT-PCR. Furthermore, we measured the effect of therapeutic administration of IFN? in HCV-infected subjects to model the effect of IFN? on chronic immune activation. IFN-I bioactivity was significantly increased in plasma of untreated HIV-1-infected subjects relative to uninfected subjects (p = 0.012), and IFN? was the predominant IFN-I subtype correlating with IFN-I bioactivity (r = 0.658, p<0.001). IFN? was not detectable in plasma of subjects receiving anti-retroviral therapy. Elevated expression of IFN? mRNA was limited to lymph node tissue cells, suggesting that peripheral blood leukocytes are not a major source of IFN? in untreated chronic HIV-1 infection. Plasma IFN-I levels correlated inversely with CD4 T cell count (p = 0.003) and positively with levels of plasma HIV-1 RNA and CD38 expression on CD8 T cells (p = 0.009). In hepatitis C virus-infected subjects, treatment with IFN-I and ribavirin increased expression of CD38 on CD8 T cells (p = 0.003). These studies identify IFN? derived from lymph nodes, rather than blood leukocytes, as a possible source of the IFN-I signature that contributes to immune activation in HIV-1 infection.
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Dynamics of Immune Reconstitution and Activation Markers in HIV+ Treatment-Naïve Patients Treated with Raltegravir, Tenofovir Disoproxil Fumarate and Emtricitabine.
PLoS ONE
PUBLISHED: 01-01-2013
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The dynamics of CD4+ T cell reconstitution and changes in immune activation and inflammation in HIV-1 disease following initiation of antiretroviral therapy (ART) are incompletely defined and their underlying mechanisms poorly understood.
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The Toll-like receptor 1/2 agonists Pam(3) CSK(4) and human ?-defensin-3 differentially induce interleukin-10 and nuclear factor-?B signalling patterns in human monocytes.
Immunology
PUBLISHED: 09-08-2011
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Human ?-defensin 3 (hBD-3) activates antigen-presenting cells through Toll-like receptors (TLRs) 1/2. Several TLR1/2 agonists have been identified but little is known about how they might differentially affect cellular activation. We compared the effects of hBD-3 with those of another TLR1/2 agonist, Pam(3) CSK(4) , in human monocytes. Monocytes incubated with hBD-3 or Pam(3) CSK(4) produced interleukin-6 (IL-6), IL-8 and IL-1?, but only Pam(3) CSK(4) induced IL-10. The IL-10 induction by Pam(3) CSK(4) caused down-modulation of the co-stimulatory molecule, CD86, whereas CD86 expression was increased in monocytes exposed to hBD-3. Assessment of signalling pathways linked to IL-10 induction indicated that mitogen-activated protein kinases were activated similarly by hBD-3 or Pam(3) CSK(4) , whereas the non-canonical nuclear factor-?B pathway was only induced by Pam(3) CSK(4) . Our data suggest that the lack of non-canonical nuclear factor-?B signalling by hBD-3 could contribute to the failure of this TLR agonist to induce production of the anti-inflammatory cytokine, IL-10, in human monocytes.
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Frequencies of FoxP3+ naive T cells are related to both viral load and naive T cell proliferation responses in HIV disease.
J. Leukoc. Biol.
PUBLISHED: 06-07-2011
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HIV infection results in depletion and dysfunction of naïve CD4(+) T cells. The mechanisms underlying these deficiencies are not understood. We investigated the frequencies of CD4(+) naïve subsets in HIV disease as defined by expression of CD25 and/or FoxP3 and the relationship of these frequencies to naïve T cell proliferation function. We observed increased proportions of CD25(+)FoxP3(+) and CD25(+)FoxP3(-) cells and decreased proportions of CD25(-)FoxP3(-) cells within the naïve CD4(+) cell compartment from HIV-infected persons compared with findings in healthy donors. These perturbations were related to higher plasma HIV RNA levels but not with higher immune activation, as measured by the proportions of CD38(+) memory CD4(+) T cells. Naïve T cell proliferation responses to mitogen stimulation were inversely related to the frequencies and absolute numbers of FoxP3(+) naïve T cells. MDA, a marker of oxidative stress, and sCD14, a marker of monocyte activation and a surrogate for microbial translocation, were increased in serum samples from HIV(+) donors; however, neither marker was related to naïve T cell function in HIV(+) donors. These observations suggest that alterations in naïve T cell subset frequencies could contribute to naïve T cell dysfunction in HIV disease, but these alterations are not necessarily the result of chronic immune activation.
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Effects of maraviroc and efavirenz on markers of immune activation and inflammation and associations with CD4+ cell rises in HIV-infected patients.
PLoS ONE
PUBLISHED: 04-29-2010
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Maraviroc treatment for HIV-1 infected patients results in larger CD4(+) T cell rises than are attributable to its antiviral activity alone. We investigated whether this is due to modulation of T cell activation and inflammation.
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Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation.
Blood
PUBLISHED: 10-14-2009
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HIV infection is associated with an increased risk of thrombosis; and as antiretroviral therapy has increased the lifespan of HIV-infected patients, their risk for cardiovascular events is expected to increase. A large clinical study found recently that all-cause mortality for HIV(+) patients was related to plasma levels of interleukin-6 and to D-dimer products of fibrinolysis. We provide evidence that this elevated risk for coagulation may be related to increased proportions of monocytes expressing cell surface tissue factor (TF, thromboplastin) in persons with HIV infection. Monocyte TF expression could be induced in vitro by lipopolysaccharide and flagellin, but not by interleukin-6. Monocyte expression of TF was correlated with HIV levels in plasma, with indices of immune activation, and with plasma levels of soluble CD14, a marker of in vivo lipopolysaccharide exposure. TF levels also correlated with plasma levels of D-dimers, reflective of in vivo clot formation and fibrinolysis. Thus, drivers of immune activation in HIV disease, such as HIV replication, and potentially, microbial translocation, may activate clotting cascades and contribute to thrombus formation and cardiovascular morbidities in HIV infection.
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Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome.
Blood
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The mechanisms responsible for increased cardiovascular risk associated with HIV-1 infection are incompletely defined. Using flow cytometry, in the present study, we examined activation phenotypes of monocyte subpopulations in patients with HIV-1 infection or acute coronary syndrome to find common cellular profiles. Nonclassic (CD14(+)CD16(++)) and intermediate (CD14(++)CD16(+)) monocytes are proportionally increased and express high levels of tissue factor and CD62P in HIV-1 infection. These proportions are related to viremia, T-cell activation, and plasma levels of IL-6. In vitro exposure of whole blood samples from uninfected control donors to lipopolysaccharide increased surface tissue factor expression on all monocyte subsets, but exposure to HIV-1 resulted in activation only of nonclassic monocytes. Remarkably, the profile of monocyte activation in uncontrolled HIV-1 disease mirrors that of acute coronary syndrome in uninfected persons. Therefore, drivers of immune activation and inflammation in HIV-1 disease may alter monocyte subpopulations and activation phenotype, contributing to a pro-atherothrombotic state that may drive cardiovascular risk in HIV-1 infection.
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Microbial translocation, immune activation, and HIV disease.
Trends Microbiol.
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The advent of combination antiretroviral therapy (cART) has significantly improved the prognosis of human immunodeficiency virus (HIV)-infected individuals. However, individuals treated long-term with cART still manifest increased mortality compared to HIV-uninfected individuals. This increased mortality is closely associated with inflammation, which persists in cART-treated HIV-infected individuals despite levels of plasma viremia below detection limits. Chronic, pathological immune activation is a key factor in progression to acquired immunodeficiency syndrome (AIDS) in untreated HIV-infected individuals. One contributor to immune activation is microbial translocation, which occurs when microbial products traverse the tight epithelial barrier of the gastrointestinal tract. Here we review the mechanisms underlying microbial translocation and its role in contributing to immune activation and disease progression in HIV infection.
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Membrane damage and repair in primary monocytes exposed to human ?-defensin-3.
J. Leukoc. Biol.
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Interactions of AMPs with plasma membranes of primary human immune cells are poorly characterized. Analysis of PI exclusion as a measure of membrane integrity indicated that hBD-3 caused membrane perturbations in monocytes but not T or B cells at concentrations typically used to kill bacteria or to induce activation of APCs. Bleb-like structures were observed in monocytes exposed to hBD-3. These cells also increased surface expression of LAMP1, a membrane repair marker after exposure to hBD-3. Furthermore, cell death was enhanced by adding an inhibitor of membrane repair. Removal of cholesterol from membranes resulted in greater susceptibility of cells to hBD-3, but cholesterol content was not different between the cell types, as assessed by filipin staining. Freshly isolated monocytes expressed higher levels of the negatively charged phospholipid, PS, on their outer leaflet compared with B or T cells. Preincubation of monocytes with molecules that bind PS protected these cells from hBD-3-induced membrane damage, suggesting that outer-membrane PS expression can at least partially explain monocyte susceptibility to hBD-3. The potential for membrane disruption caused by AMPs should be evaluated in various cell types when considering these molecules for therapeutic applications in humans.
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Diminished responsiveness to human ?-defensin-3 and decreased TLR1 expression on monocytes and mDCs from HIV-1-infected patients.
J. Leukoc. Biol.
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hBD-3 is an antimicrobial peptide that may contribute to adaptive immune responses by activating professional APCs via a TLR1/2-dependent mechanism. Patients with HIV disease experience increased susceptibility to mucosal infections, which may, in part, stem from diminished APC function. Our current studies demonstrate a reduced capacity of hBD-3 to induce the expression of a costimulatory molecule, CD80, on monocytes and mDCs from HIV-infected persons compared with cells from healthy controls. Although the expression of TLR1 and TLR2 on monocytes was not a strong predictor of hBD-3 responsiveness in bivariate analyses, monocytes and mDCs from HIV-infected persons expressed significantly lower levels of TLR1. Monocyte expression of the activation marker CD69, in cells from HIV-infected persons with therapeutically controlled viremia, was correlated directly with TLR2 and TLR4 expression but not with TLR1 expression. Overall, these studies suggest that immune activation may affect TLR2 and TLR4 expression but may not fully account for reduced TLR1 expression in monocytes from HIV-infected persons. Impairments in hBD-3 responsiveness and TLR1 expression are likely to contribute to increased risk of mucosal infection in HIV disease.
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HIV-1 is not a major driver of increased plasma IL-6 levels in chronic HIV-1 disease.
J. Acquir. Immune Defic. Syndr.
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Increased plasma IL-6 levels have been associated with HIV-1 disease progression risk, yet the drivers of IL-6 production in HIV-1 infection are not known. This study was designed to explore the relationship between HIV-1 replication and IL-6 induction.
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Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism.
J. Immunol.
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MgSO(4) exposure before preterm birth is neuroprotective, reducing the risk of cerebral palsy and major motor dysfunction. Neonatal inflammatory cytokine levels correlate with neurologic outcome, leading us to assess the effect of MgSO(4) on cytokine production in humans. We found reduced maternal TNF-? and IL-6 production following in vivo MgSO(4) treatment. Short-term exposure to a clinically effective MgSO(4) concentration in vitro substantially reduced the frequency of neonatal monocytes producing TNF-? and IL-6 under constitutive and TLR-stimulated conditions, decreasing cytokine gene and protein expression, without influencing cell viability or phagocytic function. In summary, MgSO(4) reduced cytokine production in intrapartum women, term and preterm neonates, demonstrating effectiveness in those at risk for inflammation-associated adverse perinatal outcomes. By probing the mechanism of decreased cytokine production, we found that the immunomodulatory effect was mediated by magnesium and not the sulfate moiety, and it was reversible. Cellular magnesium content increased rapidly upon MgSO(4) exposure, and reduced cytokine production occurred following stimulation with different TLR ligands as well as when magnesium was added after TLR stimulation, strongly suggesting that magnesium acts intracellularly. Magnesium increased basal I?B? levels, and upon TLR stimulation was associated with reduced NF-?B activation and nuclear localization. These findings establish a new paradigm for innate immunoregulation, whereby magnesium plays a critical regulatory role in NF-?B activation, cytokine production, and disease pathogenesis.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.