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HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection

Nature volume 424, pages 213–219 (2003)Cite this article

Abstract

All primate lentiviruses (HIV-1, HIV-2, SIV) encode Nef proteins, which are important for viral replication and pathogenicity in vivo1,2,3. It is not known how Nef regulates these processes. It has been suggested that Nef protects infected cells from apoptosis and recognition by cytotoxic T lymphocytes4,5,6. Other studies suggest that Nef influences the activation state of the infected cell, thereby enhancing the ability of that cell to support viral replication7,8,9,10. Here we show that macrophages that express Nef or are stimulated through the CD40 receptor release a paracrine factor that renders T lymphocytes permissive to HIV-1 infection. This activity requires the upregulation of B-cell receptors involved in the alternative pathway of T-lymphocyte stimulation. T lymphocytes stimulated through this pathway become susceptible to viral infection without progressing through the cell cycle. We identify two proteins, soluble CD23 and soluble ICAM, that are induced from macrophages by Nef and CD40L, and which mediate their effects on lymphocyte permissivity. Our results reveal a mechanism by which Nef expands the cellular reservoir of HIV-1 by permitting the infection of resting T lymphocytes.

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Figure 1: Macrophages expressing Nef render lymphocytes permissive to HIV-1 replication.
Figure 2: Nef and CD40 promote resting T-lymphocyte infection by regulating co-stimulatory receptors on B lymphocytes.
Figure 3: Identification of Nef and CD40-regulated B-lymphocyte receptors that overcome blocks to virus production.
Figure 4: Induction of lymphocyte permissivity by Nef and CD40 is mediated by sCD23 and sICAM.
Figure 5: Mechanistic model for induction of lymphocyte permissivity by Nef and CD40.

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Acknowledgements

We thank A. Dauphin, and K. Triques for research support, B. Blais for FACS analysis, B. Mellor for preparation of the figures, and T. Pinkos and N. Nelson for manuscript preparation. We also wish to acknowledge assay support provided by the University of Massachusetts Center for AIDS Research. The recombinant IκBα expression plasmid was kindly provided by R. Gaynor; the IκBαSR and LacZ adenovirus vectors were kindly provided by A. Baldwin. HIV-1SFI and HIV-1HSA were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. This study was supported by grants from the NIH and the Jenner Foundation to M.S.

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  1. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts, 01605, USA

    Simon Swingler, Beda Brichacek, Jean-Marc Jacque, Catherine Ulich, Jin Zhou & Mario Stevenson

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  1. Simon Swingler
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Correspondence to Mario Stevenson.

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Swingler, S., Brichacek, B., Jacque, JM. et al. HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection. Nature 424, 213–219 (2003). https://doi.org/10.1038/nature01749

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