Highly active antiretroviral therapy (HAART) can control HIV-1 replication1,2, but suboptimal treatment allows for the evolution of resistance and rebound viremia3,4,5,6,7,8. A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and the selection of regimens that maximally suppress replication. Here we show that current measures of antiviral activity, including IC50 and inhibitory quotient, neglect a key dimension, the dose-response curve slope. Using infectivity assays with wide dynamic range, we show that this slope has noteworthy effects on antiviral activity. Slope values are class specific for antiviral drugs and define intrinsic limitations on antiviral activity for some classes. Nucleoside reverse transcriptase inhibitors and integrase inhibitors have slopes of ∼1, characteristic of noncooperative reactions, whereas non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors unexpectedly show slopes >1. Instantaneous inhibitory potential (IIP), the log reduction in single-round infectivity at clinical drug concentrations, is strongly influenced by slope and varies by >8 logs for anti-HIV drugs. IIP provides a more accurate measure of antiviral activity and in general correlates with clinical outcomes. Only agents with slopes >1 achieve high-level inhibition of single-round infectivity, a finding with profound implications for drug and vaccine development.
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We thank healthy blood donors for their participation. We thank the AIDS Research and Reference Reagent Program of the US National Institutes of Health and Merck for providing anti–HIV-1 drugs. We thank C. Flexner, A. Mildvan, J. Gallant, G. Lucas, J. Cofrancesco, J. Bartlett, D. Hazuda and R. Moore for helpful discussions and critical review of the manuscript. This work was supported by the US National Institutes of Health grants AI43222 and AI51178, by the Doris Duke Charitable Foundation and by the Howard Hughes Medical Institute.
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