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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Change history
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This Letter has been retracted.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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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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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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DOI: https://doi.org/10.1038/nm1778
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