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Journal of Virology, August 2008, p. 7837-7845, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00660-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Impaired Naive and Memory B-Cell Responsiveness to TLR9 Stimulation in Human Immunodeficiency Virus Infection

Wei Jiang,^1* Michael M. Lederman,¹ Richard J. Mohner,¹ Benigno Rodriguez,¹ Todd M. Nedrich,¹ Clifford V. Harding,² and Scott F. Sieg¹

Division of Infectious Diseases, Center For AIDS Research, Department of Medicine, Case Western Reserve University and University Hospital of Cleveland, Cleveland, Ohio 44106,¹ Department of Pathology, Center For AIDS Research, Case Western Reserve University, Cleveland, Ohio 44106²

Received 25 March 2008/ Accepted 23 May 2008

Toll-like receptor 9 (TLR9) agonists such as unmethylated bacterial CpG DNAs activate B lymphocytes directly, potentially influencing their function and homeostasis. To assess B-cell responsiveness to TLR9 agonists in human immunodeficiency virus (HIV) disease, we examined the ability of naive and memory B cells to proliferation and to increase surface expression of CD80 in response to CpG oligonucleotides (ODN). CpG ODN induced expression of CD80 similarly in B cells from HIV-infected persons and from healthy controls. In contrast, proliferation responses to CpG ODN were markedly impaired in both naive and memory B-cell subsets from HIV-infected persons. Naive B-cell proliferation defects were related to plasma HIV RNA and, among memory B cells, to the frequencies of CD21-negative cells. Importantly, TLR9 mRNA levels were significantly diminished in freshly prepared naive B cells and especially so in memory B cells from HIV-positive viremic donors, suggesting a possible underlying mechanism for the observed functional impairments. Dose-response studies indicated that optimal induction of CD80 expression was achieved with much lower concentrations of CpG ODN than optimal induction of proliferation. We propose that the relatively low threshold of activation that is required for CD80 induction by CpG ODN might explain the preservation of this response in B cells from HIV-infected persons despite diminished TLR9 expression. Impaired responsiveness to TLR9 agonists may contribute to defects in humoral immunity in HIV infection.

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* Corresponding author. Mailing address: Case Western Reserve University, Medical School, BRB1048B, 2109 Adelbert Road, Cleveland, OH 44106. Phone: (216) 368-4853. Fax: (216) 368-5415. E-mail: wei.jiang{at}case.edu

Published ahead of print on 4 June 2008.

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Journal of Virology, August 2008, p. 7837-7845, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00660-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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