Cyclophilin A regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells.
The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein binds most members of the cyclophilin family of peptidyl-prolyl isomerases. Of 15 known human cyclophilins, cyclophilin A (CypA) has been the focus of investigation because it was detected in HIV-1 virions. To determine whether CypA promotes HIV-1 replication, we deleted the gene encoding CypA (PPIA) in human CD4(+) T cells by homologous recombination. HIV-1 replication in PPIA(-/-) cells was decreased and not inhibited further by cyclosporin or gag mutations that disrupt Gag's interaction with cyclophilins, indicating that no other cyclophilin family members promote HIV-1 replication. The defective replication phenotype was specific for wild-type HIV-1 since HIV-2/SIV isolates, as well as HIV-1 bearing a gag mutation that confers cyclosporin resistance, replicated the same in PPIA(+/+) and PPIA(-/-) cells. Stable re-expression of CypA in PPIA(-/-) cells restored HIV-1 replication to an extent that correlated with steady-state levels of CypA. Finally, virions from PPIA(-/-) cells possessed no obvious biochemical abnormalities but were less infectious than virions from wild-type cells. These data formally demonstrate that CypA regulates the infectivity of HIV-1 virions.
Department of Microbiology, Columbia University College of Physicians and Surgeons, 701 W. 168th Street, New York, NY 10032, USA.
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Braaten
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Luban
D002470:Cell Survival; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015683:Gene Products, gag / Q000378:metabolism; D018390:Gene Targeting; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity*; D006801:Humans; D019169:Jurkat Cells; D016296:Mutagenesis; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000166:cytology / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects
D015683:Gene Products, gag; D021984:Cyclophilin A