Inhibition of HIV-1 replication by cyclosporine A or related compounds correlates with the ability to disrupt the Gag-cyclophilin A interaction.
The HIV-1 Gag polyprotein specifically incorporates the cellular peptidylprolyl isomerase cyclophilin A into virions. HIV-1 replication is inhibited by cyclosporine A, an immunosuppressive drug which binds with high affinity to cyclophilin A and precludes interaction with the Gag polyprotein. Using a panel of four drugs, including cyclosporine A, two nonimmunosuppressive analogues of cyclosporine A which bind to cyclophilin A but which cannot form a tertiary complex with the calcium-dependent phosphatase calcineurin, and the structurally unrelated immunosuppressant FK506, we demonstrated that the antiviral effect of cyclosporine A is not due to blockade of calcineurin-mediated signal transduction pathways. Rather, the effectiveness of cyclosporine A and related compounds at inhibiting HIV-1 replication correlates with cyclophilin A-binding affinity and with the ability to disrupt the interaction between cyclophilin A and the HIV-1 Gag polyprotein. These results support the contention that the Gag-cyclophilin A interaction is required for HIV-1 replication.
Franke
E K
EK
Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Luban
J
J
D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015683:Gene Products, gag / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D019696:Peptidylprolyl Isomerase; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D002352:Carrier Proteins; D003524:Cyclosporins; D015683:Gene Products, gag; D011993:Recombinant Fusion Proteins; C070951:cyclosporin A, MeAla(6)-; D016572:Cyclosporine; D054303:HIV Reverse Transcriptase; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus