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¹ Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
² Human Genome Sciences Inc., Rockville, MD 20850
³ Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A1, Canada

Address correspondence to Susan Moir, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Rm. 6A02, 10 Center Dr., Bethesda, MD 20892. Phone: (301) 402-4559; Fax: (301) 402-5920; email: smoir{at}niaid.nih.gov

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.

Key Words: terminal differentiation • interferon • immune activation • gene expression • microarray

Abbreviations used in this paper: BLyS, B lymphocyte stimulator; FasL, Fas ligand; ISG, IFN-stimulated gene; SLE, systemic lupus erythematosus; TNFSF, TNF superfamily.

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