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Research Article

Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells

Lionel Berthoux, Sarah Sebastian, Elena Sokolskaja, and Jeremy Luban
PNAS October 11, 2005 102 (41) 14849-14853; https://doi.org/10.1073/pnas.0505659102
Lionel Berthoux
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Sarah Sebastian
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Elena Sokolskaja
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Jeremy Luban
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  1. Edited by John M. Coffin, Tufts University School of Medicine, Boston, MA, and approved August 30, 2005 (received for review July 5, 2005)

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Abstract

The peptidyl-prolyl isomerase cyclophilin A (CypA) embraces an exposed, proline-rich loop on HIV-1 capsid (CA) and renders reverse transcription complexes resistant to an antiviral activity in human cells. A CypA fusion with TRIM5 that is unique to New World owl monkeys also targets HIV-1 CA, but this interaction potently inhibits infection. A similar block to HIV-1 infection in Old World monkeys is attributable to the α isoform of the TRIM5 orthologue in these species. To determine whether HIV-1 restriction by Old World monkey TRIM5α is modulated by the CA-CypA interaction, RNA interference was used to disrupt CypA in cells from African green monkeys and rhesus macaques. HIV-1 infectivity increased in response to CypA knock-down to the same extent that it increased in response to TRIM5 knock-down. CypA knock-down eliminated the HIV-1 stimulatory effect of cyclosporin A (CsA), a competitive inhibitor of the CypA-CA interaction, or of CA mutants that block binding to CypA but caused no change in titer of retroviruses that don't interact with CypA. Simultaneous knock-down of both CypA and TRIM5 caused minimal additional increase in titer, suggesting that CypA inhibits HIV-1 replication in these cells because it is required for CA recognition by TRIM5α. Finally, CsA increased HIV-1 titer in otherwise nonrestrictive feline cells but only after these cells were transduced with Old World monkey TRIM5α. Thus, CypA is required for HIV-1 restriction by Old World monkey orthologues of TRIM5α.

  • restriction
  • retrovirus
  • capsid
  • cyclosporin A
  • RNA interference

Footnotes

  • ↵ ‡ To whom correspondence should be addressed. E-mail: jl45{at}columbia.edu.

  • This paper was submitted directly (Track II) to the PNAS office.

  • Abbreviations: AGM, African green monkey; CsA, cyclosporin A; CypA, cyclophilin A; CA, capsid; MLV, murine leukemia virus; SIV, simian immunodeficiency virus; VSV G, vesicular stomatitis virus glycoprotein; shRNA, short hairpin RNA; EIAV, equine infectious anemia virus.

  • Freely available online through the PNAS open access option.

  • Copyright © 2005, The National Academy of Sciences
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Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells
Lionel Berthoux, Sarah Sebastian, Elena Sokolskaja, Jeremy Luban
Proceedings of the National Academy of Sciences Oct 2005, 102 (41) 14849-14853; DOI: 10.1073/pnas.0505659102

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Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells
Lionel Berthoux, Sarah Sebastian, Elena Sokolskaja, Jeremy Luban
Proceedings of the National Academy of Sciences Oct 2005, 102 (41) 14849-14853; DOI: 10.1073/pnas.0505659102
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Proceedings of the National Academy of Sciences of the United States of America: 102 (41)
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