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Published on: January 22, 2019
CpG oligodeoxynucleotides activate HIV replication in latently infected human T cells
Carsten Scheller1, Anett Ullrich, Kirsty McPherson
1Institute of Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, 97078 Würzburg. scheller@vim.uni-wuerzburg.de
Insights
CpG oligodeoxynucleotides (CpG ODNs) reactivate latent HIV in human T cells by activating Toll-like receptor 9 (TLR9). This discovery offers new strategies for targeting HIV reservoirs in patients.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- CpG oligodeoxynucleotides (CpG ODNs) are known immune stimulants that engage Toll-like receptor 9 (TLR9).
- Latent human immunodeficiency virus (HIV) infection establishes reservoirs that are difficult to eradicate.
- Understanding factors that can reactivate latent HIV is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the effects of CpG ODNs on latent HIV infection in human T cells.
- To determine if CpG ODNs can stimulate HIV replication through TLR9 signaling.
- To explore the potential of CpG ODNs in targeting latent HIV reservoirs.
Main Methods:
- Treatment of latently HIV-infected T cell lines (ACH-2, J1.1) and productively infected T cells (A3.01) with specific CpG ODNs.
- Assessment of HIV replication and viral reactivation.
- Inhibition studies using chloroquine to confirm TLR9 involvement.
- Analysis of NF-kappaB activation.
Main Results:
- CpG ODNs stimulated HIV replication in ACH-2 cells and productively infected A3.01 cells, but not in Jurkat J1.1 cells.
- CpG-induced reactivation was blocked by chloroquine, confirming TLR9 mediation.
- CpG ODN treatment activated NF-kappaB in both infected and uninfected T cells, independent of proviral infection.
- TLR9-induced signal transduction pathways were activated by CpG ODNs.
Conclusions:
- CpG ODNs directly activate NF-kappaB and reactivate latent HIV in susceptible human T cell lines.
- CpG ODNs act as direct stimulators of HIV replication.
- These findings suggest a novel role for CpG ODNs in targeting latent HIV reservoirs for eradication in treated patients.
Abstract:
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.
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