A Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIVdrugs

Department of Medicine, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA.
Nature medicine (Impact Factor: 27.36). 07/2008; 14(7):762-6. DOI: 10.1038/nm1777
Source: PubMed


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.

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Available from: Karen S Anderson, Sep 15, 2014
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    • "KPT-185 potently suppresses HIV-1 replication in primary cells at nanomolar concentrations, which are far below concentrations at which cellular toxicity is reached, resulting in a favorable therapeutic index (selectivity index ≈ 850). Importantly, the dose–response curve (Fig. 1B) displays a steep slope, which is a major determinant for inhibitory potential and in general correlates with good clinical outcome (Shen et al., 2008). Genome editing using CRISPR-Cas9 in combination with homology directed repair allowed us to generate a homozygous cell line expressing mutant XPO1 containing the Cys to Ser mutation at position 528. "
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    ABSTRACT: Infection with human immunodeficiency virus (HIV) compromises the body's immune system leaving infected individuals vulnerable to other pathologies including cancer. Some forms of cancer typically develop in AIDS patients, as for example the very aggressive and most often deadly primary effusion lymphoma (PEL). There is currently no standard treatment for PEL but the use of anti-HIV drugs is associated with better prognosis. Here we show in preclinical tests that inhibitors of nuclear export suppress both HIV replication as well as PEL progression. These findings provide a rationale for further evaluating these inhibitors as treatment strategy for dual HIV/lymphoma therapy.
    08/2015; 18(9). DOI:10.1016/j.ebiom.2015.07.041
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    • "Next, to compare the inhibitory efficacy between the two types of HIV-1 infection pathways more accurately, we determined the instantaneous inhibitory potential (IIP) of each drug. IIP, defined by the EC 50 values and the slope determined by a dose–response inhibitory curve, can provide precise information about the inhibitory potency of drugs (Sampah et al., 2011; Shen et al., 2008). To directly compare the differences among classes of inhibitory drugs, the fold change of IIPs between cell-to-cell and cell-free infection conditions was calculated for each drug at its highest concentration tested. "
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    ABSTRACT: The infection routes of HIV-1 can affect several viral properties, including dissemination, pathogenesis, and immune evasion. In this study, we evaluated the inhibitory activity of a wide variety of anti-HIV drugs, focusing on the impact that different infection pathways have on their efficacy. Compared to cell-free infection, inhibitory activities were reduced in cell-to-cell productive transmission for all drugs tested. We detected weak reporter-expressing target cells after cell-to-cell transmission in the presence of integrase strand transfer inhibitors (INSTIs). Further analysis revealed that this expression was mainly due to unintegrated circular HIV (cHIV) DNAs, consisting of 1-LTR and 2-LTR circles. When in vitro-constructed cHIV DNAs were introduced into cells, the production of infectious and intercellular transmittable virions was observed, suggesting that cHIV DNA could be a source of infectious virus. These results highlight some advantages of the cell-to-cell infection mode for viral expansion, particularly in the presence of anti-retroviral drugs. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 07/2015; 484:364-376. DOI:10.1016/j.virol.2015.06.029 · 3.32 Impact Factor
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    • "Considering HIV infection and replication in hepatocytes [16] [17] [20] and CD4+ cells [21] [22] [23] as well as macrophages, [11] [19], this study used a mathematical model Table 1: Medication and corresponding parameter values. í µí±š and IC 50 are from Supplementary Table 1 of [30]. "
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    11/2014; 2014. DOI:10.1155/2014/659675
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