Inhibition of HIV-1 replication by cyclosporine A or related compounds correlates with the ability to disrupt the Gag-cyclophilin A interaction

Virology. 1996 Aug 1;222(1):279-82. doi: 10.1006/viro.1996.0421.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Isomerases / antagonists & inhibitors*
  • Amino Acid Isomerases / metabolism
  • Antiviral Agents / pharmacology*
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Cyclosporine / pharmacology*
  • Cyclosporins / pharmacology
  • Dose-Response Relationship, Drug
  • Gene Products, gag / antagonists & inhibitors*
  • Gene Products, gag / metabolism
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / physiology
  • Humans
  • Peptidylprolyl Isomerase
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / metabolism
  • Tacrolimus / pharmacology
  • Tumor Cells, Cultured
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Carrier Proteins
  • Cyclosporins
  • Gene Products, gag
  • Recombinant Fusion Proteins
  • cyclosporin A, MeAla(6)-
  • Cyclosporine
  • HIV Reverse Transcriptase
  • Amino Acid Isomerases
  • Peptidylprolyl Isomerase
  • Tacrolimus