Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Hazenberg, M.D. et al. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood 95, 249–255 (2000).

    Article  PubMed  CAS  Google Scholar 

  2. Hellerstein, M.K. et al. Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. J. Clin. Invest. 112, 956–966 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Finkel, T.H. et al. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat. Med. 1, 129–134 (1995).

    Article  PubMed  CAS  Google Scholar 

  4. Moir, S. et al. Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily. J. Exp. Med. 200, 587–599 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Kottilil, S. et al. Enhanced susceptibility to CD95-mediated natural killer cell death and turnover induced by HIV viremia. J. Acquir. Immune Defic. Syndr. 46, 151–159 (2007).

    Article  PubMed  Google Scholar 

  6. Barron, M.A., Blyveis, N., Palmer, B.E., MaWhinney, S. & Wilson, C.C. Influence of plasma viremia on defects in number and immunophenotype of blood dendritic cell subsets in human immunodeficiency virus 1–infected individuals. J. Infect. Dis. 187, 26–37 (2003).

    Article  PubMed  Google Scholar 

  7. Grossman, Z., Meier-Schellersheim, M., Paul, W.E. & Picker, L.J. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat. Med. 12, 289–295 (2006).

    Article  PubMed  CAS  Google Scholar 

  8. Giorgi, J.V. et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J. Infect. Dis. 179, 859–870 (1999).

    Article  PubMed  CAS  Google Scholar 

  9. Hahn, B.H., Shaw, G.M., De Cock, K.M. & Sharp, P.M. AIDS as a zoonosis: scientific and public health implications. Science 287, 607–614 (2000).

    Article  PubMed  CAS  Google Scholar 

  10. Gordon, S.N. et al. Short-lived infected cells support virus replication in naturally SIV-infected sooty mangabeys: implications for AIDS pathogenesis. J. Virol. 82, 3725–3735 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Gordon, S.N. et al. Severe depletion of mucosal CD4+ T cells in AIDS-free simian immunodeficiency virus–infected sooty mangabeys. J. Immunol. 179, 3026–3034 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Sumpter, B. et al. Correlates of preserved CD4+ T cell homeostasis during natural, nonpathogenic simian immunodeficiency virus infection of sooty mangabeys: implications for AIDS pathogenesis. J. Immunol. 178, 1680–1691 (2007).

    Article  PubMed  CAS  Google Scholar 

  13. Silvestri, G. et al. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 18, 441–452 (2003).

    Article  PubMed  CAS  Google Scholar 

  14. Silvestri, G. et al. Divergent host responses during primary simian immunodeficiency virus SIVsm infection of natural sooty mangabey and nonnatural rhesus macaque hosts. J. Virol. 79, 4043–4054 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

    Article  PubMed  CAS  Google Scholar 

  16. Coates, P.T. et al. Dendritic cell subsets in blood and lymphoid tissue of rhesus monkeys and their mobilization with Flt3 ligand. Blood 102, 2513–2521 (2003).

    Article  PubMed  CAS  Google Scholar 

  17. Fonteneau, J.F. et al. Human immunodeficiency virus type 1 activates plasmacytoid dendritic cells and concomitantly induces the bystander maturation of myeloid dendritic cells. J. Virol. 78, 5223–5232 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Biron, C.A. Interferons α and β as immune regulators—a new look. Immunity 14, 661–664 (2001).

    Article  PubMed  CAS  Google Scholar 

  19. Kolumam, G.A., Thomas, S., Thompson, L.J., Sprent, J. & Murali-Krishna, K. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J. Exp. Med. 202, 637–650 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Liu, Y.J. IPC: professional type 1 interferon–producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275–306 (2005).

    Article  PubMed  CAS  Google Scholar 

  21. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987–995 (2004).

    Article  PubMed  CAS  Google Scholar 

  22. Beignon, A.S. et al. Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor–viral RNA interactions. J. Clin. Invest. 115, 3265–3275 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Meier, A. et al. MyD88-dependent immune activation mediated by human immunodeficiency virus type 1–encoded Toll-like receptor ligands. J. Virol. 81, 8180–8191 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Barrat, F.J. et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J. Exp. Med. 202, 1131–1139 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Pichlmair, A. & Reis e Sousa, C. Innate recognition of viruses. Immunity 27, 370–383 (2007).

    Article  PubMed  CAS  Google Scholar 

  26. Herbeuval, J.P. et al. Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: role of type I IFN–producing plasmacytoid dendritic cells. Proc. Natl. Acad. Sci. USA 102, 13974–13979 (2005).

    Article  PubMed  CAS  Google Scholar 

  27. Honda, K. et al. IRF-7 is the master regulator of type I interferon–dependent immune responses. Nature 434, 772–777 (2005).

    Article  PubMed  CAS  Google Scholar 

  28. Tamura, T., Yanai, H., Savitsky, D. & Taniguchi, T. The IRF family transcription factors in immunity and oncogenesis. Annu. Rev. Immunol. 26, 535–584 (2008).

    Article  PubMed  CAS  Google Scholar 

  29. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Markowitz, M. et al. A novel antiviral intervention results in more accurate assessment of human immunodeficiency virus type 1 replication dynamics and T cell decay in vivo. J. Virol. 77, 5037–5038 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Giavedoni, L.D., Velasquillo, M.C., Parodi, L.M., Hubbard, G.B. & Hodara, V.L. Cytokine expression, natural killer cell activation and phenotypic changes in lymphoid cells from rhesus macaques during acute infection with pathogenic simian immunodeficiency virus. J. Virol. 74, 1648–1657 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Ferlazzo, G. Natural killer and dendritic cell liaison: recent insights and open questions. Immunol. Lett. 101, 12–17 (2005).

    Article  PubMed  CAS  Google Scholar 

  33. Barry, A.P. et al. Depletion of CD8+ cells in sooty mangabey monkeys naturally infected with simian immunodeficiency virus reveals limited role for immune control of virus replication in a natural host species. J. Immunol. 178, 8002–8012 (2007).

    Article  PubMed  CAS  Google Scholar 

  34. Dunham, R. et al. The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus. Blood 108, 209–217 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Kamath, A.T., Sheasby, C.E. & Tough, D.F. Dendritic cells and NK cells stimulate bystander t cell activation in response to TLR agonists through secretion of IFN-α, IFN-β and IFN-γ. J. Immunol. 174, 767–776 (2005).

    Article  PubMed  CAS  Google Scholar 

  36. Jego, G. et al. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 19, 225–234 (2003).

    Article  PubMed  CAS  Google Scholar 

  37. Reis e Sousa, C. Toll-like receptors and dendritic cells: for whom the bug tolls. Semin. Immunol. 16, 27–34 (2004).

    Article  PubMed  CAS  Google Scholar 

  38. Marie, I., Smith, E., Prakash, A. & Levy, D.E. Phosphorylation-induced dimerization of interferon regulatory factor 7 unmasks DNA binding and a bipartite transactivation domain. Mol. Cell. Biol. 20, 8803–8814 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Honda, K., Yanai, H., Takaoka, A. & Taniguchi, T. Regulation of the type I IFN induction: a current view. Int. Immunol. 17, 1367–1378 (2005).

    Article  PubMed  CAS  Google Scholar 

  40. Sato, M. et al. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction. Immunity 13, 539–548 (2000).

    Article  PubMed  CAS  Google Scholar 

  41. Zhang, S.Y. et al. Human Toll-like receptor–dependent induction of interferons in protective immunity to viruses. Immunol. Rev. 220, 225–236 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Binder, D., Fehr, J., Hengartner, H. & Zinkernagel, R.M. Virus-induced transient bone marrow aplasia: major role of interferon-αβ during acute infection with the noncytopathic lymphocytic choriomeningitis virus. J. Exp. Med. 185, 517–530 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Lin, Q., Dong, C. & Cooper, M.D. Impairment of T and B cell development by treatment with a type I interferon. J. Exp. Med. 187, 79–87 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Heikenwalder, M. et al. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat. Med. 10, 187–192 (2004).

    Article  PubMed  CAS  Google Scholar 

  45. Wang, T. et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med. 10, 1366–1373 (2004).

    Article  PubMed  CAS  Google Scholar 

  46. Gowen, B.B. et al. TLR3 deletion limits mortality and disease severity due to phlebovirus infection. J. Immunol. 177, 6301–6307 (2006).

    Article  PubMed  CAS  Google Scholar 

  47. Le Goffic, R. et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus–induced acute pneumonia. PLoS Pathog. 2, e53 (2006).

    Article  PubMed  CAS  Google Scholar 

  48. Herbeuval, J.P. & Shearer, G.M. HIV-1 immunopathogenesis: how good interferon turns bad. Clin. Immunol. 123, 121–128 (2007).

    Article  PubMed  CAS  Google Scholar 

  49. Kaser, A., Nagata, S. & Tilg, H. Interferon α augments activation-induced T cell death by upregulation of Fas (CD95/APO-1) and Fas ligand expression. Cytokine 11, 736–743 (1999).

    Article  PubMed  CAS  Google Scholar 

  50. Hyrcza, M.D. et al. Distinct transcriptional profiles in ex vivo CD4+ and CD8+ T cells are established early in human immunodeficiency virus type 1 infection and are characterized by a chronic interferon response as well as extensive transcriptional changes in CD8+ T cells. J. Virol. 81, 3477–3486 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Sedaghat, A.R. et al. Chronic CD4+ T cell activation and depletion in human immunodeficiency virus type I infection: type I interferon-mediated disruption of T cell dynamics. J. Virol. 82, 1870–1883 (2008).

    Article  PubMed  CAS  Google Scholar 

  52. Tilton, J.C. et al. Human immunodeficiency virus viremia induces plasmacytoid dendritic cell activation in vivo and diminished α interferon production in vitro. J. Virol. 82, 3997–4006 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Bosinger, S.E. et al. Gene expression profiling of host response in models of acute HIV infection. J. Immunol. 173, 6858–6863 (2004).

    Article  PubMed  CAS  Google Scholar 

  54. Brenchley, J.M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med. 12, 1365–1371 (2006).

    Article  PubMed  CAS  Google Scholar 

  55. Pandrea, I.V. et al. Acute loss of intestinal CD4+ T cells is not predictive of simian immunodeficiency virus virulence. J. Immunol. 179, 3035–3046 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Decalf, J. et al. Plasmacytoid dendritic cells initiate a complex chemokine and cytokine network and are a viable drug target in chronic HCV patients. J. Exp. Med. 204, 2423–2437 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Stewart, T.A. Neutralizing interferon α as a therapeutic approach to autoimmune diseases. Cytokine Growth Factor Rev. 14, 139–154 (2003).

    Article  PubMed  CAS  Google Scholar 

  58. Bochud, P.-Y.M.B., Telenti, A. & Calandra, T. Innate immunogenetics: a tool for exploring new frontiers of host defence. Lancet Infect. Dis. 7, 531–542 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Picker, L.J. et al. Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J. Exp. Med. 200, 1299–1314 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Rossio, J.L. et al. Inactivation of human immunodeficiency virus type 1 infectivity with preservation of conformational and functional integrity of virion surface proteins. J. Virol. 72, 7992–8001 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  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

Authors
  1. Judith N Mandl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ashley P Barry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas H Vanderford
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natalia Kozyr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rahul Chavan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sara Klucking
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Franck J Barrat
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert L Coffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Silvija I Staprans
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark B Feinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Mark B Feinberg.

Ethics declarations

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.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.1871

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing