期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 41, 页码 14849-14853出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0505659102
关键词
restriction; retrovirus; capsid; cyclosporin A; RNA interference
资金
- NIAID NIH HHS [R01 AI036199, R01 AI36199] Funding Source: Medline
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 a isoform of the TRIMS orthologue in these species. To determine whether HIV-1 restriction by Old World monkey TRIM5 alpha 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 TRIMS 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 TRIM5 alpha. Finally, CsA increased HIV-1 titer in otherwise nonrestrictive feline cells but only after these cells were transduced with Old World monkey TRIM5 alpha. Thus, CypA is required for HIV-1 restriction by Old World monkey orthologues of TRIM5 alpha.
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