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

Abstract

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.

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

“…Moreover, we reported that HIV-1-directed release of type-I IFN by pDCs plays a determinant role in BAFF production by monocytes (30). As shown in Fig.…”

“…We previously reported that the release of type-I IFN by pDCs following exposure to HIV-1 drives BAFF expression in human monocytes (30). These results motivated us to investigate whether HIV-1 could also modulate BAFF production in macrophages, because they represent another important cellular source of BAFF (35,36,(44)(45)(46)(47) and are, contrary to monocytes, permissive to productive HIV-1 infection (48).…”

“…Interestingly, membrane-bound BAFF has been reported to be increased on mature dendritic cells and monocytic precursors in HIV-1-infected patients (17). Moreover, we established that HIV-1 increases cell-associated BAFF in classical and intermediate monocytes (30). Therefore, we analyzed cell-associated BAFF (both membrane-bound and intracellular protein) by flow cytometry in MDMs after infection with HIV-1 ( Fig.…”

“…Multiple groups have found a correlation between increased levels of BAFF and B cell abnormalities in the context of HIV-1 infection (17-21, 28, 29). In a recent study, we established that HIV-1 promotes BAFF secretion in monocytes by a type-I IFN-dependent process (30). Moreover, we identified plasmacytoid dendritic cells (pDCs) as the cellular source of this type-I IFN-directed modulatory effect in our monocyte cultures.…”

“…1A, BAFF mRNA levels were not increased in MDMs early postinfection (i.e., 24 to 72 h) with fully infectious R5-tropic NL4-3Balenv viruses compared with uninfected control cells. The TLR3 agonist poly(I:C) and IFN-a were used as positive controls in the current studies due to their known capacity to upregulate BAFF expression in different cell types, including macrophages (25,30,49,50). Next, we assessed BAFF secretion in MDM supernatants at similar time points using a commercial ELISA kit.…”