Abstract
Cell-free human T-lymphotropic virus type 1 (HTLV-1) virions are poorly infectious in vitro for their primary target cells, CD4+ T cells. Here, we show that HTLV-1 can efficiently infect myeloid and plasmacytoid dendritic cells (DCs). Moreover, DCs exposed to HTLV-1, both before and after being productively infected, can rapidly, efficiently and reproducibly transfer virus to autologous primary CD4+ T cells. This DC-mediated transfer of HTLV-1 involves heparan sulfate proteoglycans and neuropilin-1 and results in long-term productive infection and interleukin-2–independent transformation of the CD4+ T cells. These studies, along with observations of HTLV-1–infected DCs in the peripheral blood of infected individuals, indicate that DCs have a central role in HTLV-1 transmission, dissemination and persistence in vivo. In addition to altering the current paradigm concerning how HTLV-1 transmission occurs, these studies suggest that impairment of DC function after HTLV-1 infection plays a part in pathogenesis.
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Acknowledgements
We are grateful to L. Yang, M. Liu and C.-Z. Giam (Uniformed Services University of Health Sciences) for reagents; O. Unsong and S. Jacobson (National Institute of Neurological Disorders and Stroke, National Institutes of Health) for PBMCs from the HTLV-1–infected individual; C. Pique, G. Trinchieri and D. Klinman for critical review of the manuscript; S. Reynolds for technical assistance; and P. Green, V. KewalRamani and C.-Z. Giam for helpful discussions. This project has been funded in whole or in part with federal funds from the US National Cancer Institute and US National Institutes of Health under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. This research was supported in part by the Intramural Research Program of the US National Institutes of Health, US National Cancer Institute and Center for Cancer Research.
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K.S.J. and F.W.R. designed the experiments, performed data analysis and wrote the manuscript. C.P.-S., Y.K.H. and D.C.B. prepared the reagents, conducted the experiments and edited the manuscript.
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Jones, K., Petrow-Sadowski, C., Huang, Y. et al. Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4+ T cells. Nat Med 14, 429–436 (2008). https://doi.org/10.1038/nm1745
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DOI: https://doi.org/10.1038/nm1745
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