Cyclophilin A is required for TRIM5{alpha}-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 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.
Berthoux
Lionel
L
Departments of Microbiology and Medicine, Columbia University, 701 West 168th Street, New York, NY 10032, USA.
Sebastian
Sarah
S
Sokolskaja
Elena
E
Luban
Jeremy
J
D000818:Animals; D002415:Cats; D002460:Cell Line; D002522:Chlorocebus aethiops; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1; D007113:Immunity, Innate / Q000276:immunology*; D008253:Macaca mulatta; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference; D044767:Ubiquitin-Protein Ligases
D017931:DNA Primers; D011506:Proteins; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases; D021984:Cyclophilin A