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

Maame Efua S. Sampah, Lin Shen, Benjamin L. Jilek, Robert F. Siliciano

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)7613-7618
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number18
DOIs
StatePublished - May 3 2011

Keywords

  • Evolution
  • HIV/AIDS
  • Highly active antiretroviral therapy
  • Pharmacology
  • Virology

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance'. Together they form a unique fingerprint.

Cite this