Human immunodeficiency virus type 1 entry inhibitors PRO 542 and T-20 are potently synergistic in blocking virus-cell and cell-cell fusion

Human immunodeficiency virus type 1 (HIV- 1) entry proceeds via a cascade o f events that afford promising targets for therapy. PRO 542 neutralizes HIV - 1 by blocking its attachment to CD4 cells, and T- 20 blocks gp41- mediate d fusion. Both drugs have shown promise in phase 1/ 2 clinical trials. Here , the drugs were tested individually and in combination in preclinical mode ls of HIV- 1 infection, and inhibition data were analyzed for cooperativity by using the combination index method. Synergistic inhibition of virus- ce ll and cell- cell fusion was observed for phenotypically diverse viruses fo r a broad range of drug concentrations, often resulting in greater than or equal to 10- fold dose reductions in vitro. Additional mechanism- of- actio n studies probed the molecular basis of the synergies. The markedly enhance d activity observed for the PRO 542: T- 20 combination indicates that the m ultistep nature of HIV- 1 entry leaves the virus particularly vulnerable to combinations of entry inhibitors. These findings provide a strong rational e for evaluating combinations of these promising agents for therapy in vivo .