NDLI: Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Content Provider	PubMed Central
Author	Sampah, Maame Efua S. Shen, Lin Jilek, Benjamin L. Siliciano, Robert F.
Abstract	HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC50 caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC50 , however, and inhibition at clinical concentrations can only be predicted from IC50 if the shape of the dose–response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose–response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC50 . For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC50 is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC50 , and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC50 , does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose–response curve slope.
Related Links	http://dx.doi.org/10.1073/pnas.1018360108
Ending Page	7618
Page Count	6
Starting Page	7613
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	18
Volume Number	108
Language	English
Publisher	National Academy of Sciences
Publisher Date	2011-05-03
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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