Human Immunodeficiency Virus Type 1 Entry Inhibitors PRO 542 and T-20 Are Potently Synergistic in Blocking Virus-Cell and Cell-Cell Fusion

• Published in: The Journal of infectious diseases Vol. 183; no. 7; pp. 1121 - 1125
• Main Authors: Nagashima, Kirsten A., Thompson, Daniah A. D., Rosenfield, Soraya I., Maddon, Paul J., Dragic, Tatjana, Olson, William C.
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University of Chicago Press 01.04.2001; University of Chicago Press
• Subjects: Animals; Anti-HIV Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antivirals; Biological and medical sciences; CD4 antigen; CD4 Immunoadhesins - pharmacology; Cell Fusion; Cell Line; Cell lines; CHO Cells; Concise Communications; Cricetinae; Dosage; Dose-Response Relationship, Drug; Drug Synergism; Drug synergy; Eukaryotic Cells - pathology; Eukaryotic Cells - virology; glycoprotein gp41; HeLa Cells; HIV; HIV 1; HIV Envelope Protein gp41 - pharmacology; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus 1; Human viral diseases; Humans; Infections; Infectious diseases; Medical sciences; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; PRO 542; T lymphocytes; T-20; T-Lymphocytes - virology; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Virus Replication - drug effects; Viruses; Human; Immunopathology; HIV-1 virus; Retroviridae; AIDS; Cell fusion; Lentivirus; Immune deficiency; Infection; Virus; Treatment; Viral disease; T-Lymphocyte; Models; Molecular probe; Human immunodeficiency virus; Concentrate; Mechanism of action; Virus penetration; Neutralization
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/319284

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 ⩾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