title: A role for TLR signaling during B cell activation in antiretroviral-treated HIV individuals.
abstract: The mechanisms underlying B cell activation that persists during antiretroviral therapy (ART) are unknown. Toll-like receptor (TLR) signaling is a critical mediator of innate cell activation and though B cells express TLRs, few studies have investigated a role for TLR signaling in B cell activation during HIV infection. We addressed this question by assessing the activated phenotype and TLR expression/responsiveness of B cells from ART-treated HIV-infected subjects (HIVART(+)). We evaluated activation markers implicated in B cell-mediated T cell trans infection during HIV pathogenesis. We found no significant difference in TLR expression between B cells of HIVART(+) and HIV(-) subjects. However, B cells of HIVART(+) subjects exhibited heightened endogenous expression levels of IL-6 (p=0.0051), T cell cognate ligands CD40 (p=0.0475), CD54 (p=0.0229), and phosphorylated p38 (p<0.0001), a marker of TLR signaling. In vitro, B cells of HIVART(+) individuals were less responsive to TLR stimulation compared to B cells of HIV(-) subjects. The activated phenotype of in vitro TLR-stimulated B cells of HIV(-) subjects was similar to ex vivo B cells from HIVART(+) individuals. TLR2 stimulation was a potent mediator of B cell activation, whereas B cells were least responsive to TLR4 stimulation. Compared to HIV(-) subjects, the serum level of lipoteichoic acid (TLR2 ligand) in HIVART(+) subjects was significantly higher (p=0.0207), correlating positively with viral load (p=0.0127, r=0.6453). Our data suggest that during HIV infection TLR-activated B cells may exert a pathogenic role and B cells from HIVART(+) subjects respond to in vitro TLR stimulation, yet exhibit a TLR tolerant phenotype suggesting prior in vivo TLR stimulation.
authors.affiliation: 1 Rush University Medical Center , Chicago, Illinois.
authors.forename: Basile
authors.initials: B
authors.lastname: Siewe
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
authors.forename: Audrey
authors.initials: A
authors.lastname: French
authors.forename: Patricia
authors.initials: P
authors.lastname: Demarais
authors.forename: Alan
authors.initials: A
authors.lastname: Landay
mesh_terms: D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D044966:Anti-Retroviral Agents; D051193:Toll-Like Receptors