Cyclophilin A regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells

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Abstract
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.