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Edited by John M. Coffin, Tufts University School of Medicine, Boston, MA, and approved August 30, 2005 (received for review July 5, 2005)
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.
Footnotes
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↵ ‡ To whom correspondence should be addressed. E-mail: jl45{at}columbia.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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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.
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Freely available online through the PNAS open access option.
- Copyright © 2005, The National Academy of Sciences
- Departments of *Microbiology and †Medicine, Columbia University, 701 West 168th Street, New York, NY 10032
-
Edited by John M. Coffin, Tufts University School of Medicine, Boston, MA, and approved August 30, 2005 (received for review July 5, 2005)
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
Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells
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