Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Siliciano and his colleagues propose a new index for measuring the antiviral activity of anti-HIV drugs in vitro, which suggests that there are limitations to the efficacy of antiviral drugs on the basis of their mechanism of action. They suggest that the new index is a more accurate way of measuring antiviral activity and that it correlates well with clinical outcomes. 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.