Blood B Lymphocyte Stimulator (BLyS)/BAFF levels may reflect natural immunity to HIV in highly exposed uninfected Beninese Commercial Sex Workers

Sabourin-Poirier, Catherine; Fourcade, Lyvia; Chagnon-Choquet, Josiane; Labbé, Annie‐Claude; Alary, Michel; Poudrier, Johanne; Roger, Michel

doi:10.1038/srep32318

Cited by 18 publications

(41 citation statements)

References 46 publications

(73 reference statements)

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“…Elucidating the underlying mechanisms of immunological deficits in HIV-1-infected children will help in designing effective interventional strategies. Earlier studies have reported defects in DCs leading to alterations in B cell subsets in HIV-1-infected individuals ( 30 , 35 , 43 , 44 ). An inverse correlation between BLyS (BAFF) released by mDCs and B cell numbers has been shown during primary HIV-1 infection ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

“…There is limited information on phenotypic and functional defects of DCs, B cells and DC mediated alterations in B cell subsets in pediatric HIV-1 infection and disease progression ( 15 , 17 , 25 , 27 , 28 , 35 , 36 ). Independent studies have reported lower percentages of DCs and linked DC-mediated alterations of B cell subsets with faster disease progression ( 32 ), while preservation of HIV-1 specific memory B cells is associated with efficient viral neutralization in elite controllers (ECs) ( 37 ).…”

Section: Introductionmentioning

confidence: 99%

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Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children

et al. 2017

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Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in less than 10–20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function. In this study, a total of 38 vertically transmitted HIV-1 infected antiretroviral therapy (ART) naïve children and 25 seronegative controls were recruited. Based on the CD4 counts and years post-infection, infected children were categorized as long-term non-progressors (LTNPs) (n = 20) and progressors (n = 18). Eight of these progressors were followed up at 6–12 months post-ART. Percentages (%) of DCs, B cell subsets, and expression of BLyS on DCs were analyzed by flow-cytometry. Plasma levels of B cell growth factors were measured by ELISA and viral neutralization activity was determined using TZM-bl assay. Lower (%) of myeloid DCs (mDCs), plasmacytoid DCs, and high expression of BLyS on mDCs were observed in HIV-1 infected progressors than seronegative controls. Progressors showed lower % of naive B cells, resting memory B cells and higher % of mature activated, tissue-like memory B cells as compared to seronegative controls. Higher plasma levels of IL-4, IL-6, IL-10, and IgA were observed in progressors vs. seronegative controls. Plasma levels of IgG were high in progressors and in LTNPs than seronegative controls, suggesting persistence of hypergammaglobulinemia at all stages of disease. High plasma levels of BLyS in progressors positively correlated with poor viral neutralizing activity. Interestingly on follow up, treatment naïve progressors, post-ART showed increase in resting memory B cells along with reduction in plasma BLyS levels that correlated with improvement in viral neutralization. This is the first study to demonstrate that reduction in plasma BLyS levels correlates with restoration of B cell function, in terms of viral neutralization in HIV-1-infected children.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children

et al. 2017

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“…Study subjects and sample processing Cryopreserved peripheral blood mononuclear cells (PBMCs) were obtained from a study of commercial sex workers in Cotonou, Benin. HIV-1-infected women were enrolled from a sexworker clinic and HIV-1-uninfected women were enrolled from a general health clinic, as described previously [49,50]. PBMCs were obtained from 20 untreated HIV-infected women, 20 HIV-infected women receiving ART and 10 healthy women (Table S1).…”

Section: Methodsmentioning

confidence: 99%

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

Vendrame

Seiler

Ranganath

et al. 2019

Preprint

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Objective: Our objective was to investigate the mechanisms that govern natural killer (NK) cell responses to HIV, with a focus on specific receptor-ligand interactions involved in HIV recognition by NK cells. Design and Methods: We first performed a mass cytometry-based screen of NK cell receptor expression patterns in healthy controls and HIV + individuals. We then focused mechanistic studies on the expression and function of T cell immunoreceptor with Ig and ITIM domains (TIGIT). Results: The mass cytometry screen revealed that TIGIT is upregulated on NK cells of untreated HIV + women, but not in antiretroviral-treated women. TIGIT is an inhibitory receptor that is thought to mark exhausted NK cells; however, blocking TIGIT did not improve anti-HIV NK cell responses. In fact, the TIGIT ligands CD112 and CD155 were not upregulated on CD4 + T cells in vitro or in vivo, providing an explanation for the lack of benefit from TIGIT blockade. TIGIT expression marked a unique subset of NK cells that express significantly higher levels of NK cell activating receptors (DNAM-1, NTB-A, 2B4, CD2) and exhibit a mature/adaptive phenotype (CD57 hi , NKG2C hi , LILRB1 hi , FcRγ lo , Syk lo ). Furthermore, TIGIT + NK cells had increased responses to mock-infected and HIV-infected autologous CD4 + T cells, and to PMA/ionomycin, cytokine stimulation and the K562 cancer cell line. Conclusions: TIGIT expression is increased on NK cells from untreated HIV + individuals. Although TIGIT does not participate directly in NK cell recognition of HIV, it marks a population of mature/adaptive NK cells with increased functional responses. Antibody conjugation, mass cytometry staining and data acquisitionAntibodies were conjugated using MaxPar® ×8 labeling kits (Fluidigm). To ensure antibody stability over time, antibody panels were lyophilized into single-use pellets prior to use (Biolyph). Cells were stained for mass cytometry as described previously [51,52] and resuspended in 1× EQ Beads (Fluidigm) before acquisition on a Helios mass cytometer (Fluidigm). In vitro HIV infectionReplication competent (Q23-FL) HIV-1 was made by transfection and titrated as described [51]. CD4 + T cells were activated for 2 days with plate-bound anti-CD3 (clone OKT3, eBioscience, 10 µg/ml), soluble anti-CD28/CD49d (clones L293/L25, BD Biosciences, 1 µg/ml each) and phytohemagglutinin (eBioscience, 2.5 µg/ml). CD4 + T cells were infected overnight with Q23-FL via ViroMag R/L magnetofection (Oz Biosciences) at a multiplicity of infection of 20. HIV infection was as measured by intracellular p24. TIGIT blockade assayCells were cultured in RPMI media containing 10% FBS (Thermo Fisher Scientific) and 1% penicillin/streptomycin/amphotericin (Thermo Fisher Scientific) (RP10). NK cells were incubated in 24-well plates at a concentration of 2x10 6 cells/ml in for 3 days at 37°C with 5% CO2, with addition of rhIL-2 (R&D Systems, 300 IU/ml). After 3 days, NK cells were washed with fresh media and plated in 96-well plates (80,000-100,000 cells/well). Blocking mIgG1κ anti-h...

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“…These studies suggest an association between elevated plasma BAFF and APRIL levels and hypergammaglobulinemia in HIV-infected individuals (95-99) ( Table 2). Hypergammaglobulinemia appears to be a result of a dysregulated blood B cell compartment characterized by the BAFF-induced expansion of MZ B cells (97,(100)(101)(102). Dendritic cells, monocytes, and macrophages are the sources of increased BAFF and APRIL levels during HIV infection (97, 99, 101, 103) ( Fig.…”

Section: Viruses Hivmentioning

confidence: 99%

The Role of BAFF System Molecules in Host Response to Pathogens

Sakai

Akkoyunlu

2017

Clin Microbiol Rev

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The two ligands B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) and the three receptors BAFF receptor (BAFF-R), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA) are members of the "BAFF system molecules." BAFF system molecules are primarily involved in B cell homeostasis. The relevance of BAFF system molecules in host responses to microbial assaults has been investigated in clinical studies and in mice deficient for each of these molecules. Many microbial products modulate the expression of these molecules. Data from clinical studies suggest a correlation between increased expression levels of BAFF system molecules and elevated B cell responses. Depending on the pathogen, heightened B cell responses may strengthen the host response or promote susceptibility. Whereas pathogen-mediated increases in the expression levels of the ligands and/or the receptors appear to promote microbial clearance, certain pathogens have evolved to ablate B cell responses by suppressing the expression of TACI and/or BAFF-R on B cells. Other than its well-established role in B cell responses, the TACI-mediated activation of macrophages is also implicated in resistance to intracellular pathogens. An improved understanding of the role that BAFF system molecules play in infection may assist in devising novel strategies for vaccine development.

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Blood B Lymphocyte Stimulator (BLyS)/BAFF levels may reflect natural immunity to HIV in highly exposed uninfected Beninese Commercial Sex Workers

Cited by 18 publications

References 46 publications

Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children

Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

The Role of BAFF System Molecules in Host Response to Pathogens

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