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 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.
Nagashima
K A
KA
Progenics Pharmaceuticals, Tarrytown, New York 10591, USA.
Thompson
D A
DA
Rosenfield
S I
SI
Maddon
P J
PJ
Dragic
T
T
Olson
W C
WC
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D016860:CD4 Immunoadhesins / Q000494:pharmacology*; D016466:CHO Cells; D002459:Cell Fusion; D002460:Cell Line; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000077560:Enfuvirtide; D005057:Eukaryotic Cells / Q000473:pathology / Q000821:virology; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D016860:CD4 Immunoadhesins; C096753:CD4-IgG(2); D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D000077560:Enfuvirtide