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 pepti dylprolyl isomerase cyclophilin A into virions. HIV-1 replication is i nhibited 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, t wo nonimmunosuppressive analogues of cyclosporine A which bind to cycl ophilin A but which cannot form a tertiary complex with the calcium-de pendent phosphatase calcineurin, and the structurally unrelated immuno suppressant FK506, we demonstrated that the antiviral effect of cyclos porine A is not due to blockade of calcineurin-mediated signal transdu ction pathways. Rather, the effectiveness of cyclosporine A and relate d compounds at inhibiting HIV-1 replication correlates with cyclophili n A-binding affinity and with the ability to disrupt the interaction b etween cyclophilin A and the HIV-1 Gag polyprotein. These results supp ort the contention that the Gag-cyclophilin A interaction is required for HIV-1 replication. (C) 1996 Academic Press, inc.