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

Abstract

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.

B-Cell-Activating Factor and the B-Cell Compartment in HIV/SIV Infection

“…This virus-mediated effect is essentially independent on replication since it was observed with AT2-inactivated virus. Extending our results, Gomez et al recently showed that HIV-1 does not induce BAFF expression in monocyte-derived macrophages displaying a M1 phenotype ( 92 ). Unexpectedly, our findings showed that mBAFF was expressed by a majority of pDC in healthy individuals, an expression that strongly decreased in patients with primary HIV infection.…”

A prospective study of serum microbial translocation biomarkers and risk of AIDS-related non-Hodgkin lymphoma

“…M1 typically secrete pro-inflammatory cytokines (TNFα, IL-6), while M2 mainly promote Th2 responses, immunosuppression, and tumor promotion. [31, 36] It is interesting to note that many of the cytokines or chemokines associated with AIDS-NHL risk are typically produced by M1 polarized macrophages, including IP10, TNFα, IL18, IL6 and BAFF, [31, 32, 36] which may be reflecting microbial translocation and activation of macrophages by LPS. Some notable M2 markers, including CCL17 and CD163, [31, 36] were also associated with AIDS-NHL risk, possibly reflecting the presence of tumor-associated, tumor growth-promoting, macrophages.…”

Global Mapping of the Macrophage-HIV-1 Transcriptome Reveals that Productive Infection Induces Remodeling of Host Cell DNA and Chromatin

“…Our experiments were performed with human peripheral blood monocytes that were differentiated into uncommitted/nonpolarized MØ (M0 phenotype). This information is of prime importance since the activation status of human MØ has been reported to affect HIV-1 replication 16 . Our technical procedure is based on replication-competent HIV-1 particles coding for the murine HSA cell surface molecule.…”