7th Conference - Abstract 500

Strong In Vitro Synergy Observed between the Fusion Inhibitor T-20 and a CXCR4 Blocker AMD-3100

C. TREMBLAY*¹, C. KOLLMAN¹, F. GIGUEL¹, T. C. CHOU², and M. S. HIRSCH¹. ¹Massachusetts Gen. Hosp., Harvard Med. Sch., Boston; and ²Mem. Sloan-Kettering Ctr., New York

Attachment and entry of HIV-1 into CD4 cells involves a series of events in which different viral envelope proteins interact with specific cell receptors, culminating in fusion of viral and cell membranes. Inhibitors of HIV-1 replication have been developed to act at various sites in this cascade. Combinations of agents that act at different sites in the attachment/entry process may be useful to enhance antiviral effects. AMD-3100 is a small molecule inhibitor of HIV-1 attachment to CXCR4, and T-20 is a synthetic peptide corresponding to a region of HIV-1 gp41 which blocks fusion to cell membranes. Using peripheral blood mononuclear cells infected with a CXCR4-tropic HIV-1 clinical isolate 14aPre, we evaluated drug interactions between T-20 and AMD-3100 using the median-effect principle and the combination index technique. No toxicity was observed for both agents used individually or in combination at the highest concentrations used in these experiments (T-20: 0.18 mg/ml and AMD-3100 2.025 uM). The individual 50% inhibitory concentration (IC50) for T-20 was 0.10 mg/ml and for AMD-3100 was 0.23 uM. Synergy is defined as a combination index (CI) < 1, additive effect as CI = 1 and antagonism as CI > 1. Very strong synergy was observed T-20 and AMD-3100 and this synergy increased with higher inhibitory concentrations:

Whether synergy between these two compounds in vitro will translate into clinical benefits will need to be addressed in the context of clinical trials. It will also be of interest to evaluate whether similar interactions are observed using other compounds that act on HIV-1 attachment or entry.

Key Words: Antiretroviral, Fusion, Synergy