title: Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily.
abstract: Human immunodeficiency virus (HIV) infection leads to numerous perturbations of B cells through mechanisms that remain elusive. We performed DNA microarray, phenotypic, and functional analyses in an effort to elucidate mechanisms of B cell perturbation associated with ongoing HIV replication. 42 genes were up-regulated in B cells of HIV-viremic patients when compared with HIV-aviremic and HIV-negative patients, the majority of which were interferon (IFN)-stimulated or associated with terminal differentiation. Flow cytometry confirmed these increases and indicated that CD21(low) B cells, enhanced in HIV-viremic patients, were largely responsible for the changes. Increased expression of the tumor necrosis factor (TNF) superfamily (TNFSF) receptor CD95 correlated with increased susceptibility to CD95-mediated apoptosis of CD21(low) B cells, which, in turn, correlated with HIV plasma viremia. Increased expression of BCMA, a weak TNFSF receptor for B lymphocyte stimulator (BLyS), on CD21(low) B cells was associated with a concomitant reduction in the expression of the more potent BLyS receptor, BAFF-R, that resulted in reduced BLyS binding and BLyS-mediated survival. These findings demonstrate that altered expression of genes associated with IFN stimulation and terminal differentiation in B cells of HIV-viremic patients lead to an increased propensity to cell death, which may have substantial deleterious effects on B cell responsiveness to antigenic stimulation.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. smoir@niaid.nih.gov
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.forename: Angela
authors.initials: A
authors.lastname: Malaspina
authors.forename: Oxana K
authors.initials: OK
authors.lastname: Pickeral
authors.forename: Eileen T
authors.initials: ET
authors.lastname: Donoghue
authors.forename: Joshua
authors.initials: J
authors.lastname: Vasquez
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Miller
authors.forename: Surekha R
authors.initials: SR
authors.lastname: Krishnan
authors.forename: Marie A
authors.initials: MA
authors.lastname: Planta
authors.forename: John F
authors.initials: JF
authors.lastname: Turney
authors.forename: J Shawn
authors.initials: JS
authors.lastname: Justement
authors.forename: Shyamasundaran
authors.initials: S
authors.lastname: Kottilil
authors.forename: Mark
authors.initials: M
authors.lastname: Dybul
authors.forename: JoAnn M
authors.initials: JM
authors.lastname: Mican
authors.forename: Colin
authors.initials: C
authors.lastname: Kovacs
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chun
authors.forename: Charles E
authors.initials: CE
authors.lastname: Birse
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D006801:Humans; D007372:Interferons / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017464:Receptors, Complement 3d / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D008565:Membrane Proteins; D017464:Receptors, Complement 3d; D018124:Receptors, Tumor Necrosis Factor; C435926:TNFRSF13C protein, human; C086966:TNFRSF17 protein, human; D019014:fas Receptor; D007372:Interferons