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Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors

Nature Medicine volume 9, pages 1138–1143 (2003)Cite this article

Abstract

Many mammalian species express restriction factors that confer host resistance to retroviral infection. Here we show that HIV-1 sensitivity to restriction factors is modulated by cyclophilin A (CypA), a host cell protein that binds the HIV-1 capsid protein (CA). In certain nonhuman primate cells, the CA–CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding. Conversely, disruption of CA–CypA interaction in human cells reveals that CypA protects HIV-1 from the Ref-1 restriction factor. These findings suggest that HIV-1 has co-opted a host cell protein to counteract restriction factors expressed by human cells and that this adaptation can confer sensitivity to restriction in unnatural hosts. Manipulation of HIV-1 CA recognition by restriction factors promises to advance animal models and new therapeutic strategies for HIV-1 and AIDS.

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Figure 1: Proximity of the CypA-binding loop to a potential restriction determinant.
Figure 2: Ablation of Lv-1 restriction in OMK cells by CsA.
Figure 3: A mutation in the CypA binding site ablates Lv-1 restriction in OMK cells.
Figure 4: HIV-1(G89V) is restricted by and can saturate Ref-1 in human TE671 cells.
Figure 5: Treatment of human target cells with CsA inhibits HIV-1 infection and enables HIV-1 to saturate Ref-1.
Figure 6: Ref-1 expression and CypA-dependent infection of natural HIV-1 target cells.

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Acknowledgements

We thank M. Hsu and M. Duran for PBL preparation. This work was supported by the Columbia Rockefeller Center for AIDS Research, the Donald A. Pels Charitable Trust, National Institutes of Health Grants RO1AI36199 (to J.L.) and RO1AI50111 (to P.D.B.) and a research career development fellowship 064257 from the Wellcome Trust (to G.J.T.). S.P.G. is an investigator of the Howard Hughes Medical Institute. P.D.B. is an Elizabeth Glaser Scientist of the Elizabeth Glaser Pediatric AIDS Foundation.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biophysics, Columbia University College of Physicians and Surgeons, New York, 10032, New York, USA

    Greg J Towers & Stephen P Goff

  2. Department of Immunology and Molecular Pathology, Wohl Virion Centre, Windeyer Institute, University College London, London, W1T 4JF, UK

    Greg J Towers

  3. Aaron Diamond AIDS Research Center and The Rockefeller University, 455 First Avenue, New York, 10016, New York, USA

    Theodora Hatziioannou, Simone Cowan & Paul D Bieniasz

  4. Howard Hughes Medical Institute, Columbia University College of Physicians and Surgeons, New York, 10032, New York, USA

    Stephen P Goff

  5. Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, 10032, New York, USA

    Jeremy Luban

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  1. Greg J Towers
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Correspondence to Paul D Bieniasz.

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Towers, G., Hatziioannou, T., Cowan, S. et al. Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Nat Med 9, 1138–1143 (2003). https://doi.org/10.1038/nm910

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