Mode of action of SDZ NIM 811, a nonimmunosuppressive cyclosporin A analog with activity against human immunodeficiency virus (HIV) type 1: interference with HIV protein-cyclophilin A interactions.
Cyclosporins, in particular the nonimmunosuppressive derivative SDZ NIM 811, exhibit potent anti-human immunodeficiency virus type 1 (HIV-1) activity in vitro. SDZ NIM 811 interferes at two stages of the viral replication cycle: (i) translocation of the preintegration complex to the nucleus and (ii) production of infectious virus particles. Immunosuppressive activity is not correlated with anti-HIV-1 activity of cyclosporins. However, binding to cyclophilin A, the major cellular receptor protein of cyclosporins, is a prerequisite for HIV inhibition: all structural changes of the cyclosporin A molecule leading to loss of affinity to cyclophilin abolished the antiviral effect. Cyclosporin derivatives did not interact directly with HIV-1 proteins; cyclophilin was the only detectable receptor protein for antivirally active cyclosporins. There is no evidence that inhibition of HIV occurs via a gain of function of cyclophilin in the presence of cyclosporins: the complex of cyclophilin A with SDZ NIM 811 does not bind to calcineurin or to any other viral or cellular proteins under conditions in which calcineurin binding to the cyclophilin A-cyclosporin A complex is easily detectable. Thus, the loss of function caused by binding of cyclosporins to cyclophilin seems to be sufficient for the anti-HIV effect. Cyclophilin A was demonstrated to bind to HIV-1 p24gag, and the formation of complexes was blocked by cyclosporins with 50% inhibitory concentrations of about 0.7 microM. HIV-2 and simian immunodeficiency virus are only weakly or not at all inhibited by cyclosporins. For gag-encoded proteins derived from HIV-1, HIV-2, or simian immunodeficiency virus particles, cyclophilin-binding capacity correlated with sensitivity of the viruses to inhibition by cyclosporins. Cyclophilin A also binds to HIV-1 proteins other than gag-encoded proteins, namely, p17gag, Nef, Vif, and gp120env; the biological significance of these interactions is questionable. We conclude that HIV-1 Gag-cyclophilin A interaction may be essential in HIV-1 replication, and interference with this interaction may be the molecular basis for the antiviral activity of cyclosporins.
Billich
A
A
Sandoz Forschungsinstitut GmbH, Vienna, Austria.
Hammerschmid
F
F
Peichl
P
P
Wenger
R
R
Zenke
G
G
Quesniaux
V
V
Rosenwirth
B
B
D000591:Amino Acid Isomerases / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D017931:DNA Primers; D015683:Gene Products, gag / Q000187:drug effects / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D015498:HIV-2 / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase; D011485:Protein Binding / Q000187:drug effects; D015302:Simian Immunodeficiency Virus / Q000378:metabolism
D000998:Antiviral Agents; D002352:Carrier Proteins; D017931:DNA Primers; D015683:Gene Products, gag; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase