CpG oligodeoxynucleotides activate HIV replication in latently infected human T cells.
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-kappaB 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-kappaB 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.
Scheller
Carsten
C
Institute of Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, 97078 Würzburg. scheller@vim.uni-wuerzburg.de
Ullrich
Anett
A
McPherson
Kirsty
K
Hefele
Barbara
B
Knöferle
Johanna
J
Lamla
Stefan
S
Olbrich
Anke R M
AR
Stocker
Hartmut
H
Arasteh
Keikawus
K
ter Meulen
Volker
V
Rethwilm
Axel
A
Koutsilieri
Eleni
E
Dittmer
Ulf
U
D020816:Amino Acid Motifs; D002738:Chloroquine / Q000494:pharmacology; D018899:CpG Islands; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006678:HIV / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000821:virology*; D013997:Time Factors; D051217:Toll-Like Receptor 9; D014779:Virus Replication
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D009841:Oligonucleotides; D011956:Receptors, Cell Surface; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D002738:Chloroquine