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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.

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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.

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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.

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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.

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Correspondence to Marcus Altfeld.

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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

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