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Journal of Virology, September 2007, p. 10055-10063, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00616-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Fusion of Cyclophilin A to Fv1 Enables Cyclosporine-Sensitive Restriction of Human and Feline Immunodeficiency Viruses{triangledown}

Torsten Schaller, Laura M. J. Ylinen, Benjamin L. J. Webb, Shalene Singh, and Greg J. Towers*

MRC Centre for Medical Molecular Virology, Department of Infection, Royal Free and University College London Medical School, 46 Cleveland Street, London W1T4JF, United Kingdom

Received 22 March 2007/ Accepted 26 June 2007

TRIM5{alpha} is a potent intracellular antiviral restriction factor governing species-specific retroviral replication. In the New World species owl monkey the coding region for the viral binding B30.2 domain of TRIM5{alpha} has been replaced by a cyclophilin A (CypA) pseudogene by retrotransposition. The resultant TRIM5-CypA fusion protein restricts human immunodeficiency virus type 1 (HIV-1), as well as feline immunodeficiency virus (FIV), by recruitment of the CypA domain to the incoming viral capsids. Infectivity is rescued by agents such as cyclosporine that disrupt CypA binding to its substrates. Mice encode an antiviral restriction factor called Fv1 (for Friend virus susceptibility gene 1), which is active against murine leukemia virus and related to endogenous gag sequences. Here we show that fusing CypA to Fv1 generates a restriction factor with the antiviral specificity of TRIMCyp but the antiviral properties of Fv1. Like TRIMCyp, Fv1-Cyp restricts HIV-1 and FIV and is sensitive to inhibition by cyclosporine. TRIM5{alpha} is known to have a short half-life and block infectivity before viral reverse transcription. We show that Fv1-Cyp has a long half-life and blocks after reverse transcription, suggesting that its longer half-life gives the restricted virus the opportunity to synthesize DNA, leading to a later block to infection. This notion is supported by the observation that infectivity of Fv1-Cyp restricted virus can be rescued by cyclosporine for several hours after infection, whereas virus restricted by TRIMCyp is terminally restricted after around 40 min. Intriguingly, the Fv1-Cyp-restricted HIV-1 generates closed circular viral DNA, suggesting that the restricted virus complex enters the nucleus.

* Corresponding author. Mailing address: MRC Centre for Medical Molecular Virology, Department of Infection, Royal Free and University College London Medical School, 46 Cleveland Street, London W1T 4JF, United Kingdom. Phone: 44-20 7679 9535. Fax: 44-20 7679 9555. E-mail: g.towers{at}ucl.ac.uk

{triangledown} Published ahead of print on 3 July 2007.

Journal of Virology, September 2007, p. 10055-10063, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00616-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Li, Z., Zhao, X., Bai, S., Wang, Z., Chen, L., Wei, Y., Huang, C. (2008). Proteomics Identification of Cyclophilin A as a Potential Prognostic Factor and Therapeutic Target in Endometrial Carcinoma. Mol. Cell. Proteomics 7: 1810-1823 [Abstract] [Full Text]  
  • Galla, M., Schambach, A., Towers, G. J., Baum, C. (2008). Cellular Restriction of Retrovirus Particle-Mediated mRNA Transfer. J. Virol. 82: 3069-3077 [Abstract] [Full Text]  
  • Wilson, S. J., Webb, B. L. J., Ylinen, L. M. J., Verschoor, E., Heeney, J. L., Towers, G. J. (2008). From the Cover: Independent evolution of an antiviral TRIMCyp in rhesus macaques. Proc. Natl. Acad. Sci. USA 105: 3557-3562 [Abstract] [Full Text]  


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