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J. Biol. Chem., Vol. 279, Issue 21, 21897-21902, May 21, 2004

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CpG Oligodeoxynucleotides Activate HIV Replication in Latently Infected Human T Cells^*

Carsten Scheller¶, Anett Ullrich, Kirsty McPherson||**, Barbara Hefele, Johanna Knöferle, Stefan Lamla, Anke R. M. Olbrich, Hartmut Stocker, Keikawus Arasteh, Volker ter Meulen, Axel Rethwilm, Eleni Koutsilieri¶¶, and Ulf Dittmer¶¶||||

From the Institute of Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, 97078 Würzburg, the ^||Department of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, the Institute of Virology, UK Essen, Hufelandstrasse 55, 45122 Essen, and the Vivantes Auguste-Viktoria Klinikum, Rubensstrasse 125, 12157 Berlin, Germany

CpG oligodeoxynucleotides (CpG ODNs) stimulate immune cells via the Toll-like receptor 9 (TLR9). In this study, we have investigated the effects of CpG ODNs on latent human immunodeficiency virus (HIV) infection in human T cells. Treatment of the latently infected T cell line ACH-2 with CpG ODNs 2006 or 2040 stimulated HIV replication, whereas no effects were evident when ODNs without the CpG motif were used. CpG-induced virus reactivation was blocked by chloroquine, indicating the involvement of TLR9. In contrast to the responsiveness of ACH-2 cells, CpG ODNs failed to activate HIV provirus in the latently infected Jurkat clone J1.1. We also studied the effects of CpG ODNs on productive HIV infection and found enhancement of viral replication in A3.01 T cells, whereas again no stimulating effects were observed in Jurkat T cells. CpG ODN treatment activated NF-B in ACH-2 cells, which was similarly triggered in uninfected A3.01 T cells following exposure to CpG ODNs, indicating that TLR9-induced signal transduction was not dependent on proviral infection. Our study demonstrates that CpG ODNs directly trigger the activation of NF-B and reactivation of latent HIV in human T cells. Our results point to a novel role for CpG ODNs as stimulators of HIV replication and open new avenues to eradicate the latent viral reservoirs in HIV-infected patients treated with antiretroviral therapy.

Received for publication, October 22, 2003 , and in revised form, March 4, 2004.

^* This work was supported by Grant BMBF 01 KI 0211 from the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie, Germany. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the "Competence Network HIV/AIDS, Germany."

^** Supported by Sonderforschungsbereich 465.

^¶¶ Both authors contributed equally to this study.

^|||| Supported by a grant from the Deutsche Forschungsgemeinschaft (Grant Di 714/6-1 and 6-2).

^¶ To whom correspondence should be addressed. Tel.: 49-931-201-49897; Fax: 49-931-201-49553; E-mail: scheller{at}vim.uni-wuerzburg.de.

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