期刊
JOURNAL OF INFECTIOUS DISEASES
卷 183, 期 7, 页码 1121-1125出版社
UNIV CHICAGO PRESS
DOI: 10.1086/319284
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资金
- NIAID NIH HHS [AI-43084, AI-43847] Funding Source: Medline
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 greater than or equal to 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.
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