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Identification of calcium-modulating cyclophilin ligand as a human host restriction to HIV-1 release overcome by Vpu

Nature Medicine volume 14, pages 641–647 (2008)Cite this article

A Retraction to this article was published on 01 February 2010

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Abstract

The HIV-1 Vpu protein is required for efficient viral release from human cells. For HIV-2, the envelope (Env) protein replaces the role of Vpu. Both Vpu and HIV-2 Env enhance virus release by counteracting an innate host-cell block within human cells that is absent in African green monkey (AGM) cells. Here we identify calcium-modulating cyclophilin ligand (CAML) as a Vpu-interacting host factor that restricts HIV-1 release. Expression of human CAML (encoded by CAMLG) in AGM cells conferred a strong restriction of virus release that was reversed by Vpu and HIV-2 Env, suggesting that CAML is the mechanistic link between these two viral regulators. Depletion of CAML in human cells eliminated the need for Vpu in enhancing HIV-1 and murine leukemia virus release. These results point to CAML as a Vpu-sensitive host restriction factor that inhibits HIV release from human cells. The ability of CAML to inhibit virus release should illuminate new therapeutic strategies against HIV.

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Figure 1: Interaction of HIV-1 Vpu with human CAML.
Figure 2: Human CAML blocks Vpu deletion mutant viral release in Cos-7 cells.
Figure 3: Vpu and HIV-2 Env overcome an hCAML-induced block to viral release in Cos-7 cells.
Figure 4: CAML depletion eliminates the Vpu-sensitive cellular block to viral release in restrictive HeLa cells.
Figure 5: Depletion of endogenous CAML from the E6-1 T cell line rescues vpu− mutant viral release.
Figure 6: CAML restricts MLV release.

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  • 04 February 2010

    This Letter has been retracted. See the full retraction notice for details.

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Acknowledgements

CA-specific antibodies were a gift from S. Goff (Columbia University). A. Weiss and T. Folks (US NIH AIDS Research and Reference Program) provided HeLa, Cos-7, Jurkat E6-1 and A3.01 cells. R. Bram and D. Billadeau (Mayo Clinic) provided plasmid pCMS3.eGFP.H1p. N. Landau (New York University) provided plasmid plasmid pSV-ψ-MLV-env−. This research was supported by grants from Vanderbilt-Meharry Center for AIDS Research Developmental Core funded by the US NIH (to V.V.), the Vanderbilt Department of Pediatrics (to V.V.), Building Interdisciplinary Research Careers in Women's Health (to V.V.) and the US NIH (AI058828 to P.S. and 5R01CA112414 to R.J.B). We thank S.P. Goff (Columbia University) and K. Strebel (NIH) for reagents used in the study. We thank the Center for AIDS Research cell immunopathogenesis core and Emory School of Medicine EM core for help. We also thank R.T. D'Aquila and H.E. Ruley for critical review of the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Infectious Diseases, Vanderbilt University School of Medicine, 1161 21st Avenue South, D-7235 MCN, Nashville, 37232-2581, Tennessee, USA

    Vasundhara Varthakavi, Ellen Heimann-Nichols, Rita M Smith & Yuehui Sun

  2. Department of Pediatric and Adolescent Medicine, Division of Pediatric Research Laboratories, Mayo Clinic, Mayo Medical School, 200 First Street Southwest, Rochester, 55905, Minnesota, USA

    Richard J Bram

  3. Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, 2015 Upper Gate Drive, Atlanta, 30322, Georgia, USA

    Showkat Ali, Jeremy Rose, Lingmei Ding & Paul Spearman

Authors
  1. Vasundhara Varthakavi
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  4. Yuehui Sun
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  5. Richard J Bram
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  9. Paul Spearman
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Contributions

V.V. designed and performed most aspects of this study. E.H.-N. performed biochemical assays and Y.S. generated the CAML mapping constructs with the support of V.V. R.M.S. and V.V. performed yeast two-hybrid analysis. R.J.B. generated the CAML knockdown plasmids. S.A., J.R. and L.D. conducted the microscopy and EM experiments with the support of P.S. V.V. wrote this manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Vasundhara Varthakavi or Paul Spearman.

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Varthakavi, V., Heimann-Nichols, E., Smith, R. et al. Identification of calcium-modulating cyclophilin ligand as a human host restriction to HIV-1 release overcome by Vpu. Nat Med 14, 641–647 (2008). https://doi.org/10.1038/nm1778

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