Induction of B Cell-Activating Factor by Viral Infection Is a General Phenomenon, but the Types of Viruses and Mechanisms Depend on Cell Type

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.

Section: Hiv-1 Increases Baff Expression and Secretion In Mdmsmentioning

confidence: 99%

mentioning

confidence: 99%

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

“…BAFF exists as membrane-bound protein and in a soluble form (27), which has been shown to aggregate into 3-mers or 60-mers depending on the primary structure of the protein (27)(28)(29)(30)(31)(32)(33). The cytokine is produced by hematopoietic (23) as well as by nonhematopoietic cells (34), and its expression has been found to be upregulated by proinflammatory responses (23,27,34,35), during viral infections (25,36,37), and in various autoimmune conditions (8,10,(38)(39)(40).…”

Section: Baff Concentrations In Patients With Padmentioning

confidence: 99%

Soluble BAFF Levels Inversely Correlate with Peripheral B Cell Numbers and the Expression of BAFF Receptors

Kreuzaler

Rauch

Salzer

et al. 2012

159

122

The TNF family member protein BAFF/BLyS is essential for B cell survival and plays an important role in regulating class switch recombination as well as in the selection of autoreactive B cells. In humans, increased concentrations of soluble BAFF are found in different pathological conditions, which may be as diverse as autoimmune diseases, B cell malignancies, and primary Ab deficiencies (PAD). Because the mechanisms that regulate BAFF levels are not well understood, we newly developed a set of mAbs against human BAFF to study the parameters that determine the concentrations of soluble BAFF in circulation. Patients with PAD, including severe functional B cell defects such as BTK, BAFF-R, or TACI deficiency, were found to have higher BAFF levels than asplenic individuals, patients after anti-CD20 B cell depletion, chronic lymphocytic leukemia patients, or healthy donors. In a comparable manner, mice constitutively expressing human BAFF were found to have higher concentrations of BAFF in the absence than in the presence of B cells. Therefore, our data strongly suggest that BAFF steady-state concentrations mainly depend on the number of B cells as well as on the expression of BAFF-binding receptors. Because most patients with PAD have high levels of circulating BAFF, the increase in BAFF concentrations cannot compensate defects in B cell development and function.

“…have shown also that increased BAFF levels observed in certain chronic autoimmune disorders and chronic inflammatory diseases were associated to an elevated type I IFN response (48)(49)(50). Moreover, in vitro studies have demonstrated that viruses can induce high expression of BAFF through a type I IFN pathway in different cell types (43,44). Therefore, we evaluated the possible involvement of type I IFN in the virus-directed BAFF production by human monocytes.…”

Section: Hiv-1-induced Baff Secretion In Monocytes Relies On Type I Imentioning

confidence: 97%

“…1A, BAFF mRNA levels were increased upon exposure to both NL4-3 and NL4-3Balenv (called Bal hereinafter) compared with controls (called mock hereinafter). The TLR3 agonist poly(I:C) was used as a positive control in the current studies due to its known capacity to upregulate BAFF expression in different cell types (43)(44)(45). BAFF, as other members of the TNF superfamily, can be produced as a soluble protein (23).…”

Section: Hiv-1 Increases Baff Expression and Secretion In Human Monocmentioning

confidence: 99%

HIV-1–Triggered Release of Type I IFN by Plasmacytoid Dendritic Cells Induces BAFF Production in Monocytes

Gómez

Ouellet

Tremblay

2015

HIV-1 infection leads to numerous B cell abnormalities, including hypergammaglobulinemia, nonspecific B cell activation, nonspecific class switching, increased cell turnover, breakage of tolerance, increased immature/transitional B cells, B cell malignancies, as well as a loss of capacity to generate and maintain memory, all of which contribute to a global impairment of the immune humoral compartment. Several cytokines and soluble factors, which are increased in sera of HIV-1–infected individuals, have been suggested to directly or indirectly contribute to these B cell dysfunctions, and one of these is the B cell–activating factor (BAFF). We report in this study that HIV-1 (X4- and R5-tropic) upregulates BAFF expression and secretion by human monocytes. Moreover, we show that the virus-mediated production of BAFF by monocytes relies on a type I IFN response by a small percentage of plasmacytoid dendritic cells (pDCs) present in the monocyte cultures. HIV-1–induced type I IFN by pDCs triggers BAFF production in both classical and intermediate monocytes, but not in nonclassical monocytes, which nonetheless display a very strong basal BAFF production. We report also that basal BAFF secretion was higher in monocytes obtained from females compared with those from male donors. This study provides a novel mechanistic explanation for the increased BAFF levels observed during HIV-1 infection and highlights the importance of pDC/monocyte crosstalk to drive BAFF secretion.