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PMID: 15353552 Published · ppublish English Journal Article

Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily.

The Journal of experimental medicine ·Vol. 200 ·No. 5 ·2004-09-06 ·Pages 587-99

Moir S, Malaspina A, Pickeral OK, Donoghue ET, Vasquez J, Miller NJ, Krishnan SR, Planta MA, Turney JF, Justement JS, Kottilil S, Dybul M, Mican JM, Kovacs C, Chun TW, Birse CE, Fauci AS

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.

MeSH Terms
ADP-ribosyl Cyclase/biosynthesis ADP-ribosyl Cyclase 1 Antigens, CD/biosynthesis Apoptosis B-Lymphocytes/cytology,pathology,virology Cell Differentiation Cell Membrane/metabolism Cell Separation Flow Cytometry HIV Infections/blood HIV Seropositivity Humans Interferons/metabolism Membrane Glycoproteins Oligonucleotide Array Sequence Analysis Phenotype Receptors, Complement 3d/biosynthesis Up-Regulation fas Receptor/biosynthesis
Chemicals
Antigens, CD Membrane Glycoproteins Receptors, Complement 3d fas Receptor Interferons ADP-ribosyl Cyclase CD38 protein, human ADP-ribosyl Cyclase 1
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Moir Susan
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Rm. 6A02, 10 Center Dr., Bethesda, MD 20892, USA. smoir@niaid.nih.gov
Malaspina Angela
Pickeral Oxana K
Donoghue Eileen T
Vasquez Joshua
Miller Natalie J
Krishnan Surekha R
Planta Marie A
Turney John F
Justement J Shawn
Kottilil Shyamasundaran
Dybul Mark
Mican JoAnn M
Kovacs Colin
Chun Tae-Wook
Birse Charles E
Fauci Anthony S
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20032236
Email
smoir@niaid.nih.gov
Published
2004-09-06
Pages
587-99
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2262955
Subset
IM
Corrections
RepublishedIn
PMID: 15508184
External Links
PubMed source DOI: 10.1084/jem.20032236 PMC Full Text View journal details
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