Cyclophilin a Is Required for TRIM5α-Mediated Resistance to HIV-1 in Old World Monkey Cells

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 th...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-10, Vol.102 (41), p.14849-14853
Main Authors: Lionel Berthoux, Sarah Sebastian, Elena Sokolskaja, Luban, Jeremy
Format: Article
Language:English
Subjects:
Biological Sciences
Cell lines
Cells
Complementary DNA
Cyclosporins
HIV 1
Human immunodeficiency virus 1
Infections
Macaca mulatta
Monkeys
Proteins
Retrovirus
Vero cells
Viruses
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Summary: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 TRIMSα 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 TRIMSα. Finally, CsA increased HIV-1 titer in otherwise non restrictive 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0505659102