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Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections

Nature Medicine volume 14, pages 1077–1087 (2008)Cite this article

Abstract

Pathogenic HIV infections of humans and simian immunodeficiency virus (SIV) infections of rhesus macaques are characterized by generalized immune activation and progressive CD4+ T cell depletion. In contrast, natural reservoir hosts for SIV, such as sooty mangabeys, do not progress to AIDS and show a lack of aberrant immune activation and preserved CD4+ T cell populations, despite high levels of SIV replication. Here we show that sooty mangabeys have substantially reduced levels of innate immune system activation in vivo during acute and chronic SIV infection and that sooty mangabey plasmacytoid dendritic cells (pDCs) produce markedly less interferon-α in response to SIV and other Toll-like receptor 7 and 9 ligands ex vivo. We propose that chronic stimulation of pDCs by SIV and HIV in non-natural hosts may drive the unrelenting immune system activation and dysfunction underlying AIDS progression. Such a vicious cycle of continuous virus replication and immunopathology is absent in natural sooty mangabey hosts.

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Figure 1: Muted NK cell activation and DC maturation and homing during acute SIVsm infection of sooty mangabeys compared to rhesus macaques.
Figure 2: SIV and HIV stimulate IFN-α production via TLR7 and TLR9 on pDCs.
Figure 3: IFN-α production by SM pDCs upon TLR7 or TLR9 ligand and iSIV stimulation is lower than that by RM pDCs.
Figure 4: The levels of inflammatory cytokine production upon iSIV and TLR7 or TLR9 ligand stimulation of PBMCs in RMs and SMs are similar.
Figure 5: Multiple SM-specific amino-acid substitutions are present in the transactivation domain of IRF-7.
Figure 6: Elevations in IFN-α and type I interferon responses occur in chronically SIV-infected RMs and HIV-infected humans, but not in SIV-infected SMs.

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Acknowledgements

The authors would like to thank B. Weaver, J. Skvarich, B. O'Hara and M. Mulligan for their help coordinating blood draws from HIV-infected humans, S. Ehnert and E. Strobert for their care of the study animals, B. Lawson and D. Lee for performing the SIVsm and SIVmac239 viral load assays, J. Ingersoll for performing the HIV viral load assays, A. McCrary for assistance with cloning and sequencing, K. Dalbey for help with running ELISAs, H. Yi for help with electron microscopy, J. Bess and J. Lifson at the US National Cancer Institute for providing the aldrithiol-2–inactivated SIV and HIV strains and microvesicle controls, 3M Pharmaceuticals for providing the R-848 and anonymous human volunteers for providing blood samples for these studies. We would also like to thank G. Silvestri for his input. We gratefully acknowledge the support of the US National Institutes of Health grants R01 HL075766 and R01 AI049155, the Yerkes National Primate Research Center Grant RR000165 and the Emory Center for AIDS Research Grant P30-AI-50409. The authors apologize for not citing all relevant publications due to space limitations.

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  1. Silvija I Staprans & Mark B Feinberg

    Present address: Current address: Merck Vaccines and Infectious Diseases, Merck & Co., Inc., WP97-A337, 770 Sumneytown Pike, PO Box 4, West Point, Pennsylvania 19486, USA.,

  2. Judith N Mandl and Ashley P Barry: These authors contributed equally to this work.

Authors and Affiliations

  1. Graduate Program in Population Biology, Ecology and Evolution, Emory University, 1510 Clifton Road, Atlanta, 30322, Georgia, USA

    Judith N Mandl

  2. Emory Vaccine Center and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, 30329, Georgia, USA

    Judith N Mandl, Ashley P Barry, Thomas H Vanderford, Natalia Kozyr, Rahul Chavan, Sara Klucking, Silvija I Staprans & Mark B Feinberg

  3. Dynavax Technologies, 2929 Seventh Street, Berkeley, 94710, California, USA

    Franck J Barrat & Robert L Coffman

  4. Department of Microbiology and Immunology and Department of Medicine, Emory University School of Medicine, 954 Gatewood Road, Atlanta, 30329, Georgia, USA

    Silvija I Staprans & Mark B Feinberg

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Contributions

J.N.M., A.P.B. and M.B.F. designed the experiments, and J.N.M. and A.P.B. conducted most of them. T.H.V. sequenced genes involved in the TLR signaling pathway under the supervision of S.I.S., N.K. performed gene expression analyses, R.C. and S.K. developed assays and reagents that paved the way for this work, F.J.B. and R.L.C. provided the TLR antagonists and contributed to planning inhibition experiments, and M.B.F. supervised the overall project. J.N.M., A.P.B. and M.B.F. analyzed the data and J.N.M. and M.B.F. wrote the manuscript.

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Correspondence to Mark B Feinberg.

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Competing interests

R.L.C. and F.J.B. are employed by Dynavax Technologies, which is developing inhibitors of TLR7 and TLR9 for therapeutic use.

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Supplementary Figures 1–4, Supplemetary Tables 1–3 and Supplementary Methods (PDF 1265 kb)

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Mandl, J., Barry, A., Vanderford, T. et al. Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med 14, 1077–1087 (2008). https://doi.org/10.1038/nm.1871

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