Journal
NATURE MEDICINE
Volume 14, Issue 7, Pages 762-766Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1777
Keywords
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NIAID NIH HHS [R01 AI043222-08, R01 AI051178-05, R01 AI043222-10, R37 AI051178-07, R37 AI051178, AI51178, R01 AI051178, AI43222, R01 AI043222-09, R37 AI051178-06A1, R01 AI043222] Funding Source: Medline
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Highly active antiretroviral therapy (HAART) can control HIV-1 replication(1,2), but suboptimal treatment allows for the evolution of resistance and rebound viremia(3-8). 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 IC(50) 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 similar to 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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