CTLA-4PD-1 Memory CD4 T Cells Critically Contribute to Viral Persistence in Antiretroviral Therapy-Suppressed, SIV-Infected Rhesus Macaques.

Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals but does not eliminate the reservoir of latently infected cells. Recent work identified PD-1 follicular helper T (Tfh) cells as an important cellular compartment for viral persistence. Here, using ART-treated, SIV-infected rhesus macaques, we show that CTLA-4PD-1 memory CD4 T cells, which share phenotypic markers with regulatory T cells, were enriched in SIV DNA in blood, lymph nodes (LN), spleen, and gut, and contained replication-competent and infectious virus.

Loss of immune homeostasis dictates SHIV rebound after stem-cell transplantation.

The conditioning regimen used as part of the Berlin patient's hematopoietic cell transplant likely contributed to his eradication of HIV infection. We studied the impact of conditioning in simian-human immunodeficiency virus-infected (SHIV-infected) macaques suppressed by combination antiretroviral therapy (cART). The conditioning regimen resulted in a dramatic, but incomplete depletion of CD4 and CD8 T cells and CD20 B cells, increased T cell activation and exhaustion, and a significant loss of SHIV-specific Abs.

P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART.

Peripheral CD4+ T-cell levels are not fully restored in a significant proportion of HIV+ individuals displaying long-term viral suppression on c-ART. These immunological nonresponders (INRs) have a higher risk of developing AIDS and non-AIDS events and a lower life expectancy than the general population, but the underlying mechanisms are not fully understood. We used an in vitro system to analyze the T- and B-cell potential of CD34+ hematopoietic progenitor cells.

Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques.

Despite successful control of viremia, many HIV-infected individuals given antiretroviral therapy (ART) exhibit residual inflammation, which is associated with non-AIDS-related morbidity and mortality and may contribute to virus persistence during ART. Here, we investigated the effects of IL-21 administration on both inflammation and virus persistence in ART-treated, SIV-infected rhesus macaques (RMs). Compared with SIV-infected animals only given ART, SIV-infected RMs given both ART and IL-21 showed improved restoration of intestinal Th17 and Th22 cells and a more effective reduction of immune activation in blood and intestinal mucosa, with the latter maintained through 8 months after ART interruption.

HIV "elite controllers" are characterized by a high frequency of memory CD8+ CD73+ T cells involved in the antigen-specific CD8+ T-cell response.

Human immunodeficiency virus type 1 (HIV-1) infection is characterized by chronic immune activation and suppressed T-lymphocyte functions. Here we report that CD73, both a coactivator molecule of T cells and an immunosuppressive ecto-enzyme through adenosine production, is only weakly expressed by CD8+ T cells of HIV-infected patients and only partially restored after successful antiviral treatment. CD73 expression on CD8+ T cells correlates inversely with cell activation both ex vivo and in vitro.

NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function.

Activating mutations in NOTCH1, an essential regulator of T cell development, are frequently found in human T cell acute lymphoblastic leukemia (T-ALL). Despite important advances in our understanding of Notch signal transduction, the regulation of Notch functions in the nucleus remains unclear. Using immunoaffinity purification, we identified NOTCH1 nuclear partners in T-ALL cells and showed that, beyond the well-characterized core activation complex (ICN1-CSL-MAML1), NOTCH1 assembles a multifunctional complex containing the transcription coactivator AF4p12, the PBAF nucleosome remodeling complex, and the histone demethylases LSD1 and PHF8 acting through their demethylase activity to promote epigenetic modifications at Notch-target genes.

Effect of a second, booster, influenza vaccination on antibody responses in quiescent systemic lupus erythematosus: an open, prospective, controlled study.

Objective: In SLE, a decreased antibody response on influenza vaccination has been reported. In this study, we assessed whether a booster vaccination could improve antibody responses, as determined by seroprotection rates, in SLE patients.

Methods: SLE patients (n = 52) with quiescent disease (SLEDAI < or =4) and healthy controls (HCs) (n = 28) received subunit influenza vaccine in October-December 2007.

Studies of cell-mediated immune responses to influenza vaccination in systemic lupus erythematosus.

Objective: Both antibody and cell-mediated responses are involved in the defense against influenza. In patients with systemic lupus erythematosus (SLE), a decreased antibody response to subunit influenza vaccine has been demonstrated, but cell-mediated responses have not yet been assessed. This study was therefore undertaken to assess cell-mediated responses to influenza vaccination in patients with SLE.

Cell-mediated immune responses to influenza vaccination in Wegener's granulomatosis.

Background: Both antibody and cell-mediated immune responses are involved in the defence against influenza. In Wegener's granulomatosis (WG), antibody responses to influenza vaccination appear to be similar to those in healthy controls, but cell-mediated responses have not been studied.

Objective: To determine whether cell-mediated responses to influenza vaccination in WG vary from those in controls.

Notch increases T/NK potential of human hematopoietic progenitors and inhibits B cell differentiation at a pro-B stage.

Notch and its ligands regulate multiple cell fate decisions. However, several questions on the timing, durability, and reversibility of Notch signaling effects on human hematopoietic precursors are still unresolved. Here, we used recombinant Delta ligands to deliver temporally and dose-controlled signals to human immature cord blood CD34(+)CD38(low) cells at clonal cell levels.

Notch ligands potentiate IL-7-driven proliferation and survival of human thymocyte precursors.

Notch and IL-7 are both well-characterized factors involved in T-cell development. In contrast to the mouse model, their precise requirements in the differentiation and/or proliferation of various stages of human thymic development have not been fully explored. Here, we demonstrate that IL-7 alone is sufficient to induce the differentiation of ex vivo purified CD34(+) triple negative (TN) surface (s) CD3(-) CD4(-)CD8(-) (CD3(-)CD4(-)CD8(-)), CD4 immature single positive (ISP) (sCD3(-)CD4(+)CD8(-)) and double positive (DP) (sCD3(-)CD4(+)CD8(+)) human thymic precursors to mature DP expressing sCD3 (sCD3(+)CD4(+)CD8(+)).

Cellular and molecular mechanisms of memory T-cell survival.

Long-term maintenance of the memory T-cell response is the hallmark of immune protection and, hence, constitutes one of the most important objectives of vaccine-development strategies. Persistent memory T cells, developed after vaccination or microbial infections, ensure the generation of an antimicrobial response upon re-exposure to the pathogen through rapid clonal proliferation and activation of effector functions. However, in the context of many pathogen infections, these memory T cells fail to persist and die.

Wegener's granulomatosis patients show an adequate antibody response to influenza vaccination.

Objectives: Wegener's granulomatosis (WG) is a systemic vasculitis characterised by relapsing and remitting disease activity. Immunosuppressive drugs are used to control disease, but increase susceptibility to infection. Therefore, influenza vaccination should be considered in WG patients.

Chronic hepatitis E virus infection in liver transplant recipients.

Hepatitis E virus (HEV) infection is known to run a self-limiting course. Sporadic cases of acute hepatitis due to infection with HEV genotype 3, present in pig populations, are increasingly recognized. Zoonotic transmission seems infrequent.

Swine-like hepatitis E viruses are a cause of unexplained hepatitis in the Netherlands.

Hepatitis E virus (HEV) infections in developed countries are recognized as an imported disease related to travel to endemic regions. However, increasing evidence suggests that HEV infection may also occur in the developed countries and that swine may act as a possible reservoir. To investigate the indigenous transmission of HEV in the Netherlands, sera from 50 blood donors and 1027 sera from patients with acute hepatitis were screened with an ELISA for HEV-specific IgG and IgM.

Short exposure to Notch ligand Delta-4 is sufficient to induce T-cell differentiation program and to increase the T cell potential of primary human CD34+ cells.

Objective: The Notch pathway plays a key role in cell fate choices and in T-cell development. The goal of our study was to evaluate whether a short in vitro stimulation of the Notch pathway may alter human progenitor cell behavior.

Methods: CD34+ cord blood progenitors were exposed for 4 days to either immobilized Notch ligand Delta-4 or in control conditions.

[Primary cytomegalovirus infection in the postnatal period].

A male infant born vaginally after a gestation period of 25 4/7 weeks with a birth weight of 875 g underwent surgical correction for oesophageal atresia with a distal tracheo-oesophageal fistula. Postoperative complications included seam leakage, mediastinitis with sepsis, transient elevated diaphragm, recurrent fistula and seam stenosis. Persistent ductus arteriosus was closed surgically.

Fatal illness associated with pulmonary hypertension in a neonate caused by intrauterine echovirus 11 infection.

Nonpolio enterovirus (NPEV) infections are known to cause a wide range of illnesses in the neonatal period. In most cases, NPEV is presumed to be contracted during birth. Intrauterine NPEV infections occur infrequently.

Safety and efficacy of influenza vaccination in systemic lupus erythematosus patients with quiescent disease.

Objective: to assess the safety and efficacy of influenza vaccination in patients with systemic lupus erythematosus (SLE), and to evaluate the influence of immunosuppressive drugs on the immune response.

Methods: SLE patients (n=56) and healthy controls (n=18) were studied. All patients had quiescent disease (SLE disease activity index View Article and Find Full Text PDF

Hepatitis E is a cause of unexplained hepatitis in The Netherlands.

Background: Hepatitis E virus (HEV) is the major etiologic agent of enterically transmitted viral hepatitis in much of the developing world. Evidence provided in recent years shows that HEV is also prevalent in very low numbers in non-endemic countries. Recently, a cluster of three patients with acute hepatitis E but no history of travel to endemic countries was discovered in the geographical area provided with service by the Public Health Laboratory Groningen and Drenthe, The Netherlands.