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Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14849-53. Epub 2005 Oct 3.

Cyclophilin A is required for TRIM5{alpha}-mediated resistance to HIV-1 in Old World monkey cells.

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  • 1Departments of Microbiology and Medicine, Columbia University, 701 West 168th Street, New York, NY 10032, USA.

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 alpha isoform of the TRIM5 orthologue in these species. To determine whether HIV-1 restriction by Old World monkey TRIM5alpha 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 TRIM5alpha. Finally, CsA increased HIV-1 titer in otherwise nonrestrictive feline cells but only after these cells were transduced with Old World monkey TRIM5alpha. Thus, CypA is required for HIV-1 restriction by Old World monkey orthologues of TRIM5alpha.

PMID:
16203999
[PubMed - indexed for MEDLINE]
PMCID:
PMC1239943
Free PMC Article
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