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Disulfide exchange in domain 2 of CD4 is required for entry of HIV-1

Nature Immunology volume 3, pages 727–732 (2002)Cite this article

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Abstract

CD4, a member of the immunoglobulin superfamily of receptors that mediates cell-cell interactions in the immune system, is the primary receptor for HIV-1. The extracellular portion of CD4 is a concatenation of four immunoglobulin-like domains, D1 to D4. The D1, D2 and D4 domains each contain a disulfide bond. We show here that the D2 disulfide bond is redox-active. The redox state of the thiols (disulfide versus dithiol) appeared to be regulated by thioredoxin, which is secreted by CD4+ T cells. Locking the CD4 and the thioredoxin active-site dithiols in the reduced state with a hydrophilic trivalent arsenical blocked entry of HIV-1 into susceptible cells. These findings indicate that redox changes in CD4 D2 are important for HIV-1 entry and represent a new target for HIV-1 entry inhibitors.

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Figure 1: Cell-surface CD4 contains free thiol(s).
Figure 2: The CD4 D2 disulfide is redox-active.
Figure 3: Reduction of cell-surface and soluble CD4 by thioredoxin.
Figure 4: Labeling of cell-surface CD4 with GSAO-B.
Figure 5: Inhibition of HIV-1 entry into CD4+ cells by GSAO.

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  • 09 July 2002

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Acknowledgements

We thank A. Holmgren and F. Clarke for the thioredoxins; C. LaBranche for the HIV-18xD368R Env clone; A. Maerz, H. Drummer and A. Cane for technical assistance; and A. Jaramillo and R. Ffrench for help and advice. Supported by the Australian Research Council, the National Health and Medical Research Council of Australia and the NSW Health Department.

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Authors and Affiliations

  1. University of New South Wales and Department of Haematology, Centre for Thrombosis and Vascular Research, School of Medical Sciences, Prince of Wales Hospital, Sydney, 2052, NSW, Australia

    Lisa J. Matthias, Patricia T.W. Yam, Xing-Mai Jiang, Neil Donoghue & Philip J. Hogg

  2. National Centre for HIV Virology Research, Infectious Diseases Laboratories, Institute of Medical and Veterinary Science, Adelaide, 5000, SA, Australia

    Nick Vandegraaff & Peng Li

  3. Virology Unit, St. Vincent's Institute of Medical Research, Fitzroy, 3065, VIC, Australia

    Pantelis Poumbourios

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Correspondence to Philip J. Hogg.

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Matthias, L., Yam, P., Jiang, XM. et al. Disulfide exchange in domain 2 of CD4 is required for entry of HIV-1. Nat Immunol 3, 727–732 (2002). https://doi.org/10.1038/ni815

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