HIV Nef Promotes Expression of B-Lymphocyte Stimulator by Blood Dendritic Cells During HIV Infection in Humans

Chagnon-Choquet, Josiane; Gauvin, Julie; Roger, Julien; Fontaine, Julie; Poudrier, Johanne; Roger, Michel; Vassal, Anne; Legault, Mario; Routy, Jean Pierre; Tremblay, Cécile; Thomas, Réjean; Trottier, Benôit; Vézina, Sylvie; Charest, Louise; Milne, C; Friedman, Jason; Huchet, Emmanuelle; Baril, Jean-Guy; Côté, Pierre; Lessard, Bernard; Dufresne, Simon-Frédéric; Charron, Marc-André; LeBlanc, Roger; Labrecque, Louise G.; Rouleau, Danielle; Fortin, Claude; Munoz, Melissa; Bruneau, Julie; Gilmore, Norbert; Lalonde, Richard; Potter, Martin; Klein, Marina B.; Pokomandy, Alexandra de; Szabo, Jason; Bernard, Nicole F.

doi:10.1093/infdis/jiu611

Cited by 16 publications

(36 citation statements)

References 48 publications

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“…Moreover, Nef expression in macrophages induces the release of inflammatory factors such as MIP-1a, MIP-1b, IL-6, TNF, and IL-1b, among others (64)(65)(66)(67). Of high relevance to the present work, one study has reported also that recombinant soluble Nef increases BAFF expression in monocyte-derived DCs (28). As the biological effects of recombinant proteins are sometimes dictated by factors such as dosage and purity, we chose a different approach in which MDM cultures were infected with fully replicative molecular clones of HIV-1 that differ only in their expression of Nef.…”

Section: Nef Is Dispensable For Hiv-1-mediated Baff Upregulationmentioning

confidence: 57%

“…The HIV-1 accessory protein Nef was another possible candidate that could have a role in the noticed virus-dependent BAFF secretion in MDMs because of its known capacity to induce production of several soluble factors in monocyte-macrophages (65), including BAFF in mDCs (28). However, our results using a Nef-deleted variant suggest that such virus is still able to upregulate BAFF production in MDMs.…”

Section: Hiv-1-mediated Baff Induction Is Modulated By the Macrophagementioning

confidence: 74%

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HIV-1–Mediated BAFF Secretion in Macrophages Does Not Require Endosomal TLRs, Type-I IFN, and Nef, but Depends on the Cellular Phenotype Status

Gómez

Ouellet

Deshière

et al. 2016

The Journal of Immunology

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HIV-1 infection is characterized by persistent viral replication, chronic immune activation, and CD4+ T cell depletion. Moreover, several immune dysfunctions are observed in cells that are not targeted by the virus, such as B cells. Some B cell abnormalities include hypergammaglobulinemia, nonspecific B cell activation, class switching, increased cell turnover, breakage of tolerance, and a loss of the capacity to generate and maintain memory. Several cytokines and growth factors that are increased in the serum of HIV-1–infected individuals have been suggested to directly or indirectly trigger B cell activation, and one of these is BAFF. In this study, we investigate the ability of fully competent (R5-tropic) HIV-1 to induce BAFF production by monocyte-derived macrophages (MDMs). We demonstrate here that HIV-1 drives BAFF production in MDMs in a type-I IFN– and TLR-independent manner. Moreover, we determine that HIV-1 Nef accessory protein is dispensable in BAFF upregulation as a nef-deleted HIV-1 strain is still able to increase BAFF at levels similar to the wild type strain. Finally, we show that the macrophage phenotype status affects HIV-1 replication and BAFF induction, as both were abrogated in MDMs displaying a M1 phenotype. This study provides new useful information about the increased levels of BAFF observed during HIV-1 infection and highlights the importance of macrophages as a source of BAFF, a phenomenon that might contribute to B cell dysfunctions at inflammatory tissue sites in infected individuals.

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Section: Nef Is Dispensable For Hiv-1-mediated Baff Upregulationmentioning

confidence: 57%

Section: Hiv-1-mediated Baff Induction Is Modulated By the Macrophagementioning

confidence: 74%

HIV-1–Mediated BAFF Secretion in Macrophages Does Not Require Endosomal TLRs, Type-I IFN, and Nef, but Depends on the Cellular Phenotype Status

Gómez

Ouellet

Deshière

et al. 2016

The Journal of Immunology

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“…2C) when compared to HIV-infected CSWs. For consistency and comparison with our previously published observations 161819, we have analyzed the minor fraction of CD14 + monocytes which do not express detectable levels of CD11c, separately from the bulk of CD14 + CD11c + monocytes. In fact, when compared to CD14+CD11c- monocytes, CD14+CD11c+ cell percentage greatly fluctuated in HIV+ progressors18, and these cells expressed greater levels of surface BLyS1617.…”

Section: Resultsmentioning

confidence: 89%

“…Indeed, soluble HIV-Nef can directly modulate BLyS membrane expression and soluble release by monocyte derived DCs (mo-DCs)19, and HIV-Env has been shown to upregulate BLyS expression by macrophages24. Furthermore, BLyS has been shown to be directly induced by type I IFNs2526.…”

Section: Discussionmentioning

confidence: 99%

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

Sabourin-Poirier

Fourcade

Chagnon-Choquet

et al. 2016

Sci Rep

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We have previously shown that excess B lymphocyte Stimulator (BLyS)/BAFF in plasma and on surface of blood dendritic cells (DC) of HIV-infected progressors coincides with B-cell dysregulations and increased frequencies of “precursor” innate marginal zone (MZ)-like B-cells. In contrast, both blood BLyS levels and frequencies of this population remained unaltered in HIV elite-controllers. Based on these observations, we hypothesized that control of BLyS and innate B-cell status could be associated with natural immunity against HIV infection. Therefore, we assessed blood BLyS levels and B-cell status in HIV highly-exposed commercial sex workers (CSWs) from Benin. We found blood BLyS levels of HIV-uninfected CSWs were lower than those observed in both HIV-infected CSW and HIV-uninfected non-CSW groups. Furthermore, levels of BLyS expression on blood T-cells and monocytes were lower in HIV-uninfected CSWs when compared to HIV-infected CSWs, but higher than those observed for HIV-uninfected non-CSWs. Concomitantly, HIV-infected CSWs presented a dysregulated blood B-cell compartment, characterized by increased total IgG1, increased frequencies of populations presenting immature and/or innate profiles and a higher ratio of IgG+/IgA+ plasmablasts. In contrast, relatively low levels of BLyS in the blood of HIV-uninfected CSWs coincided with a rather preserved B-cell compartment.

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“…BAFF production in innate cells is triggered directly by viral products, including double-stranded RNA (104), negative factor (Nef) (105), and the exterior envelope glycoprotein gp120 (106), and indirectly by type I interferon (IFN) secreted from plasmacytoid DCs in response to viral particles (107,108). Among the HIV molecules, Nef has been reported to induce BAFF expression in human DCs and murine macrophages, but the induction of BAFF expression by Nef is negated if the macrophages are M1 polarized (105,109). The role for gp120 in HIV infection is especially interesting because this glycoprotein not only stimulates BAFF and APRIL expression in monocytes but also engages human tonsillar IgD ϩ B cells through interactions with mannose C-type lectin receptors (MCLRs).…”

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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HIV Nef Promotes Expression of B-Lymphocyte Stimulator by Blood Dendritic Cells During HIV Infection in Humans

Cited by 16 publications

References 48 publications

HIV-1–Mediated BAFF Secretion in Macrophages Does Not Require Endosomal TLRs, Type-I IFN, and Nef, but Depends on the Cellular Phenotype Status

HIV-1–Mediated BAFF Secretion in Macrophages Does Not Require Endosomal TLRs, Type-I IFN, and Nef, but Depends on the Cellular Phenotype Status

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

The Role of BAFF System Molecules in Host Response to Pathogens

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