AEGiS-13IAC: In vitro anti-HIV-1 synergy between two CCR5 coreceptor inhibitors AOP-RANTES and TAK-779.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

In vitro anti-HIV-1 synergy between two CCR5 coreceptor inhibitors AOP-RANTES and TAK-779.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. WeOrA534)

Tremblay C, Kollman C, Giguel F, Chou TC, Hirsch MS
C. Tremblay, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA 02114, United States, Tel.: +1 617 726 38 12, Fax: +1 617 726 74 16, E-mail: ctremblay@partners.org

OBJECTIVES: Findings of residual replication-competent HIV-1 in CD4 lymphocytes despite aggressive combination antiretroviral therapy as well as the emergence of resistant virus variants highlight the need to develop new drugs targeting different sites of HIV-1 replication. A promising target is the inhibition of CCR5, a co-receptor mediating entry of M-tropic (R5) viruses into cells. AOP-RANTES, an analog of the b-chemokine RANTES, and TAK-779, a low molecular weight CCR5 antagonist are two inhibitors of CCR5 which have antiviral activity against R5 HIV-1 isolates. To define the roles of these compounds as part of combination antiretroviral therapy, we evaluated their in vitro antiviral interactions.

METHOD: Multiply-diluted fixed ratio combinations of drugs or single drugs were added to healthy donor peripheral blood mononuclear cells (PBMC) infected with an R5 HIV-1 clinical isolate. Interactions between the drugs were characterized using the median-effect principle and the combination index (CI) technique. CI > 0.9 = synergy, CI > 0.9 > 1.1 = additive, CI > 1.1 = antagonism.

RESULTS: The mean 50% inhibitory concentrations for AOP-RANTES were 7.03 é 4.59 ng/ml and for TAK-779 were 0.03 é 0.03 mg/ml. The combination of AOP-RANTES and TAK-779 showed synergy with combination indices ranging from 0.35 to 0.45 at 95% inhibitory concentration. The synergy level was similar at 75, 90 and 95% inhibitory concentrations. No in vitro toxicity was observed when using concentrations of AOP-RANTES up to 54 ng/ml and TAK-779 up to 0.14 mg/ml.

CONCLUSIONS: The combination of these two CCR5 inhibitors was synergistic against HIV-1 in vitro, without obvious toxicity. The clinical antiviral activities and toxicities of these compounds have yet to be defined. The favorable in vitro interactions seen in this study are encouraging and warrant further studies of this class of drugs with other inhibitors of the fusion process as well as other antiretrovirals.

Keywords: AEGIS, HIV-1, RANTES, Amides, Ammonium Compounds, Virus Replication, Greece, aminooxypentane-RANTES, TAK 779, In Vitro, antagonists & inhibitors, virology
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