MODE OF ACTION OF SDZ NIM-811, A NONIMMUNOSUPPRESSIVE CYCLOSPORINE-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 NI M 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. Immunos uppressive activity is not correlated with anti-HIV-1 activity of cycl osporins. However, binding to cyclophilin A, the major cellular recept or protein of cyclosporins, is a prerequisite for HIV inhibition: all structural changes of the cyclosporin A molecule leading to loss of af finity to cyclophilin abolished the antiviral effect. Cyclosporin deri vatives did not interact directly with HIV-1 proteins; cyclophilin was the only detectable receptor protein for antivirally active cyclospor ins. There is no evidence that inhibition of HIV occurs via a gain of function of cyclophilin in the presence of cyclosporins: the complex o f cyclophilin A with SDZ NIM 811 does not bind to calcineurin or to an y other viral or cellular proteins under conditions in which calcineur in binding to the cyclophilin A-cyclosporin A complex is easily detect able. Thus, the loss of function caused by binding of cyclosporins to cyclophilin seems to be sufficient for the anti-HIV effect. Cyclophili n A was demonstrated to bind to HIV-1 p24(gag), and the formation of c omplexes was blocked by cyclosporins with 50% inhibitory concentration s of about 0.7 mu M. HIV-2 and simian immunodeficiency virus are only weakly or not at all inhibited by cyclosporins. For gag-encoded protei ns derived from HIV-1, HIV-2, or simian immunodeficiency virus particl es, cyclophilin-binding capacity correlated with Sensitivity of the vi ruses to inhibition by cyclosporins. Cyclophilin A also binds to HIV-1 proteins other than gag-encoded proteins, namely, p17(gag), Nef, Vif, and gp120(env); 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 interac tion may be the molecular basis for the antiviral activity of cyclospo rins.