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

AUTOR(ES)

Braaten, Douglas

FONTE

Oxford University Press

RESUMO

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.

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