Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs.
Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but suboptimal treatment allows for the evolution of resistance and rebound viremia. 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 approximately 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.
Shen
Lin
L
Department of Medicine, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA.
Peterson
Susan
S
Sedaghat
Ahmad R
AR
McMahon
Moira A
MA
Callender
Marc
M
Zhang
Haili
H
Zhou
Yan
Y
Pitt
Eleanor
E
Anderson
Karen S
KS
Acosta
Edward P
EP
Siliciano
Robert F
RF
D019380:Anti-HIV Agents / Q000145:classification* / Q000494:pharmacology* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D004305:Dose-Response Relationship, Drug; D023581:HIV Fusion Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D019429:Integrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D023581:HIV Fusion Inhibitors; D017320:HIV Protease Inhibitors; D019429:Integrase Inhibitors; D018894:Reverse Transcriptase Inhibitors