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.

Sex differences in the Toll-like receptor–mediated response of plasmacytoid dendritic cells to HIV-1

Abstract

Manifestations of viral infections can differ between women and men1, and marked sex differences have been described in the course of HIV-1 disease. HIV-1–infected women tend to have lower viral loads early in HIV-1 infection but progress faster to AIDS for a given viral load than men2,3,4,5,6,7. Here we show substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce markedly more interferon-α (IFN-α) in response to HIV-1–encoded Toll-like receptor 7 (TLR7) ligands than pDCs derived from men, resulting in stronger secondary activation of CD8+ T cells. In line with these in vitro studies, treatment-naive women chronically infected with HIV-1 had considerably higher levels of CD8+ T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs may account for higher immune activation in women compared to men at a given HIV-1 viral load and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a new approach to reduce HIV-1–associated pathology.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Sex differences in IFN-α production of pDCs after TLR7/8 stimulation with HIV-1–derived ligands.
Figure 2: Impact of sex hormone abundance on the IFN-α production by pDCs in response to TLR7/8 agonists.
Figure 3: Sex differences in CD38 expression on CD8+ T cells after stimulation with HIV-1–derived TLR7/8 ligands is dependent on IFN-α.
Figure 4: Sex differences in the CD4+ and CD8+ T cell activation of HIV-1–infected, treatment-naive individuals.

References

  1. 1

    Fish, E.N. The X-files in immunity: sex-based differences predispose immune responses. Nat. Rev. Immunol. 8, 737–744 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Katzenstein, D.A. et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. N. Engl. J. Med. 335, 1091–1098 (1996).

    CAS  Article  Google Scholar 

  3. 3

    Farzadegan, H. et al. Sex differences in HIV-1 viral load and progression to AIDS. Lancet. 352, 1510–1514 (1998).

    CAS  Article  Google Scholar 

  4. 4

    Evans, J.S. et al. Serum levels of virus burden in early-stage human immunodeficiency virus type 1 disease in women. J. Infect. Dis. 175, 795–800 (1997).

    CAS  Article  Google Scholar 

  5. 5

    Sterling, T.R. et al. Sex differences in longitudinal human immunodeficiency virus type 1 RNA levels among seroconverters. J. Infect. Dis. 180, 666–672 (1999).

    CAS  Article  Google Scholar 

  6. 6

    Lyles, C.M. et al. Longitudinal human immunodeficiency virus type 1 load in the Italian seroconversion study: correlates and temporal trends of virus load. J. Infect. Dis. 180, 1018–1024 (1999).

    CAS  Article  Google Scholar 

  7. 7

    Gandhi, M. et al. Does patient sex affect human immunodeficiency virus levels? Clin. Infect. Dis. 35, 313–322 (2002).

    Article  Google Scholar 

  8. 8

    Fahey, J.L. et al. The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N. Engl. J. Med. 322, 166–172 (1990).

    CAS  Article  Google Scholar 

  9. 9

    Fahey, J.L. et al. Prognostic significance of plasma markers of immune activation, HIV viral load and CD4 T-cell measurements. AIDS 12, 1581–1590 (1998).

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  Google Scholar 

  11. 11

    Deeks, S.G. & Walker, B.D. The immune response to AIDS virus infection: good, bad or both? J. Clin. Invest. 113, 808–810 (2004).

    CAS  Article  Google Scholar 

  12. 12

    Deeks, S.G. et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 104, 942–947 (2004).

    CAS  Article  Google Scholar 

  13. 13

    Hunt, P.W. et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J. Infect. Dis. 197, 126–133 (2008).

    Article  Google Scholar 

  14. 14

    Sousa, A.E., Carneiro, J., Meier-Schellersheim, M., Grossman, Z. & Victorino, R.M. CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J. Immunol. 169, 3400–3406 (2002).

    CAS  Article  Google Scholar 

  15. 15

    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).

    CAS  Article  Google Scholar 

  16. 16

    Boasso, A. & Shearer, G.M. Chronic innate immune activation as a cause of HIV-1 immunopathogenesis. Clin. Immunol. 126, 235–242 (2008).

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    Chang, J.J. & Altfeld, M. TLR-mediated immune activation in HIV. Blood 113, 269–270 (2009).

    CAS  Article  Google Scholar 

  19. 19

    Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).

    CAS  Article  Google Scholar 

  20. 20

    Meier, A. et al. MyD88-dependent immune activation mediated by HIV-1-encoded TLR ligands. J. Virol. 81, 8180–8191 (2007).

    CAS  Article  Google Scholar 

  21. 21

    Berghöfer, B. et al. TLR7 ligands induce higher IFN-α production in females. J. Immunol. 177, 2088–2096 (2006).

    Article  Google Scholar 

  22. 22

    Hughes, G.C., Thomas, S., Li, C., Kaja, M.K. & Clark, E.A. Cutting edge: progesterone regulates IFN-α production by plasmacytoid dendritic cells. J. Immunol. 180, 2029–2033 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Eyster, M.E., Goedert, J.J., Poon, M.C. & Preble, O.T. Acid-labile α interferon. A possible preclinical marker for the acquired immunodeficiency syndrome in hemophilia. N. Engl. J. Med. 309, 583–586 (1983).

    CAS  Article  Google Scholar 

  24. 24

    Krown, S.E. et al. Relationship and prognostic value of endogenous interferon-α, β2-microglobulin and neopterin serum levels in patients with Kaposi sarcoma and AIDS. J. Acquir. Immune Defic. Syndr. 4, 871–880 (1991).

    CAS  Article  Google Scholar 

  25. 25

    Mildvan, D., Machado, S.G., Wilets, I. & Grossberg, S.E. Endogenous interferon and triglyceride concentrations to assess response to zidovudine in AIDS and advanced AIDS-related complex. Lancet 339, 453–456 (1992).

    CAS  Article  Google Scholar 

  26. 26

    Rodriguez, B. et al. Interferon-α differentially rescues CD4 and CD8 T cells from apoptosis in HIV infection. AIDS 20, 1379–1389 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Gandhi, R.T. et al. Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1–positive subjects: results from ACTG 384. J. Acquir. Immune Defic. Syndr. 42, 426–434 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Robbins, G.K. et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N. Engl. J. Med. 349, 2293–2303 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Sterling, T.R. et al. Initial plasma HIV-1 RNA levels and progression to AIDS in women and men. N. Engl. J. Med. 344, 720–725 (2001).

    CAS  Article  Google Scholar 

  30. 30

    Giorgi, J.V. et al. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. J. Acquir. Immune Defic. Syndr. 6, 904–912 (1993).

    CAS  PubMed  Google Scholar 

  31. 31

    Liu, Z. et al. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 16, 83–92 (1997).

    CAS  Article  Google Scholar 

  32. 32

    Boasso, A., Hardy, A.W., Anderson, S.A., Dolan, M.J. & Shearer, G.M. HIV-induced type I interferon and tryptophan catabolism drive T cell dysfunction despite phenotypic activation. PLoS One 3, e2961 (2008).

    Article  Google Scholar 

  33. 33

    Herbeuval, J.P. et al. Differential expression of IFN-α and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1–infected patients. Proc. Natl. Acad. Sci. USA 103, 7000–7005 (2006).

    CAS  Article  Google Scholar 

  34. 34

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

    CAS  Article  Google Scholar 

  35. 35

    Mandl, J.N. 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).

    CAS  Article  Google Scholar 

  36. 36

    Khatissian, E., Chakrabarti, L. & Hurtrel, B. Cytokine patterns and viral load in lymph nodes during the early stages of SIV infection. Res. Virol. 147, 181–189 (1996).

    CAS  Article  Google Scholar 

  37. 37

    Silvestri, G., Paiardini, M., Pandrea, I., Lederman, M.M. & Sodora, D.L. Understanding the benign nature of SIV infection in natural hosts. J. Clin. Invest. 117, 3148–3154 (2007).

    CAS  Article  Google Scholar 

  38. 38

    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).

    CAS  Article  Google Scholar 

  39. 39

    Guiducci, C., Coffman, R.L. & Barrat, F.J. Signalling pathways leading to IFN-α production in human plasmacytoid dendritic cell and the possible use of agonists or antagonists of TLR7 and TLR9 in clinical indications. J. Intern. Med. 265, 43–57 (2009).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank S. Deeks, P. Hunt, B. Walker and J. Spritzler for valuable intellectual input and discussions and the ACTG 384 main study and immunology A5007 substudy teams. These studies were supported by US National Institutes of Health (NIH)–National Institute of Allergy and Infectious Diseases grants to M.A. (R21 AI071806, PO1 AI074415) and G.K.R. (K01AI062435), the Harvard University Center for AIDS Research, the Bill & Melinda Gates Foundation and the Doris Duke Charitable Foundation. A.M. was supported by a fellowship from the German Research Society (Deutsche Forschungsgemeinschaft), and J.J.C. was supported by a Fellowship awarded from the National Health and Medical Research Council of Australia (519578). ACTG 384 was supported in part by National Institute of Allergy and Infectious Diseases grants AI38855, AI27659, AI38858, AI25879 and AI27666 and by Agouron/Pfizer, Bristol Myers Squibb and GlaxoSmithKline. This project has been funded in whole or in part with federal funds from the US National Cancer Institute (NCI), NIH, under Contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Support Program of the NIH, NCI, Center for Cancer Research. M.A. is a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation. We thank the Mark and Lisa Schwartz Foundation and the Phillip T. and Susan M. Ragon Foundation for their support.

Author information

Affiliations

Authors

Contributions

A.M. and J.J.C. conducted the in vitro experiments, data analysis and contributed to manuscript preparation; H.K.S., T.F.W. and R.J.L. also conducted the in vitro experiments; E.S.C., R.J.B., L.O. and D.M. contributed to the statistical analysis and interpretation of the data; A.M., J.J.C., R.J.B., G.A., H.S. and M.A. participated in the planning of the experiments; S.K. and M.C. conducted the genetic polymorphism experiments; S.B. helped with the enrollment of study subjects, R.B.P. and G.K.R. provided the data for ACTG 384; J.D.L. provided the AT-2 virus and vesicle controls used in the in vitro experiments; and M.A. planned the studies, prepared the manuscript and supervised the project.

Corresponding author

Correspondence to Marcus Altfeld.

Supplementary information

Supplementary Text and Figures

Supplementary Table 1 (PDF 196 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Meier, A., Chang, J., Chan, E. et al. Sex differences in the Toll-like receptor–mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med 15, 955–959 (2009). https://doi.org/10.1038/nm.2004

Download citation

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