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MICROBIOLOGY
Independent evolution of an antiviral TRIMCyp in rhesus macaques

Sam J. Wilson^*, Benjamin L. J. Webb^*, Laura M. J. Ylinen^*, Ernst Verschoor, Jonathan L. Heeney^,, and Greg J. Towers^*,

*Medical Research Council Centre for Medical Molecular Virology, Department of Infection, Royal Free and University College Medical School, University College London, London W1T 4JF, United Kingdom; Department of Virology, Biomedical Primate Research Centre, 288 GJ, Rijswijk, The Netherlands; and Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, United Kingdom

Edited by John M. Coffin, Tufts University School of Medicine, Boston, MA, and approved December 27, 2007 (received for review September 21, 2007)

Abstract

The antiretroviral restriction factor TRIM5 has recently emerged as an important mediator of innate immunity and species-specific inhibition of retroviral replication in mammals. Selection pressure from pathogenic infection has driven rapid evolution of TRIM5 genes, leading to the antiviral specificities we see today. Remarkably, the New World owl monkey (Aotus trivirgatus) encodes a TRIM5 protein in which the antiviral determinants in the B30.2 domain have been replaced by cyclophilin A (CypA) encoded by a retrotransposed cDNA. The owl monkey TRIMCyp protein restricts infection by a subset of lentiviruses that recruit CypA to their capsids, including HIV-1 and feline immunodeficiency virus. Here, we show that the Old World monkey, rhesus macaque (Macaca mulatta), also encodes a TRIMCyp protein that has arisen independently from that in owl monkeys. The rhesus TRIMCyp is encoded by a single, but common, allele (Mamu7) of the rhesus TRIM5 gene, among at least six further alleles that encode full-length TRIM5 proteins with no homology to CypA. The antiviral specificity of the rhesus TRIMCyp is distinct, restricting infection of HIV-2 and feline immunodeficiency virus but not HIV-1. Restriction by rhesus TRIMCyp is before reverse transcription and inhibited by blocking CypA binding, with cyclosporine A, or by mutation of the capsid CypA binding site. These observations suggest a mechanism of restriction that is conserved between TRIMCyp proteins. The lack of activity against HIV-1 suggests that Mamu7 homozygous animals will be null for TRIM5-mediated restriction of HIV-1 and could contribute to improved animal models for HIV/AIDS.

cyclophilin | lentivirus | restriction | TRIM5 | zoonosis

Author contributions: S.J.W., L.M.J.Y., J.L.H., and G.J.T. designed research; S.J.W. and B.L.J.W. performed research; L.M.J.Y., E.V., J.L.H., and G.J.T. contributed new reagents/analytic tools; S.J.W., B.L.J.W., and G.J.T. analyzed data; and G.J.T. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

To whom correspondence should be addressed. E-mail: g.towers{at}ucl.ac.uk

© 2008 by The National Academy of Sciences of the USA

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