Human immunodeficiency virus type 1 entry inhibitors PRO 542 and T-0 are potently synergistic in blocking virus-cell and cell-cell fusion

• Published in: The Journal of infectious diseases Vol. 183; no. 7; p. 1121
• Main Authors: Nagashima, Kirsten A, Thompson, Daniah A D, Rosenfield, Soraya I, Maddon, Paul J
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2001
• ISSN: 0022-1899; 1537-6613

Human immunodeficiency virus type 1 (HIV-1) entry proceeds via a cascade of events that afford promising targets for therapy. PRO 542 neutralizes HIV-1 by blocking its attachment to CD4 cells, and T-20 blocks gp41-mediated fusion. Both drugs have shown promise in phase 1/2 clinical trials. Here, the drugs were tested individually and in combination in preclinical models of HIV-1 infection, and inhibition data were analyzed for cooperativity by using the combination index method. Synergistic inhibition of virus-cell and cell-cell fusion was observed for phenotypically diverse viruses for a broad range of drug concentrations, often resulting in > or = 10-fold dose reductions in vitro. Additional mechanism-of-action studies probed the molecular basis of the synergies. The markedly enhanced activity observed for the PRO 542:T-20 combination indicates that the multistep nature of HIV-1 entry leaves the virus particularly vulnerable to combinations of entry inhibitors. These findings provide a strong rationale for evaluating combinations of these promising agents for therapy in vivo.