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Antiviral Agents

A Tight-Binding Mode of Inhibition Is Essential for Anti-Human Immunodeficiency Virus Type 1 Virucidal Activity of Nonnucleoside Reverse Transcriptase Inhibitors

Dimitrios Motakis, Michael A. Parniak
Dimitrios Motakis
Lady Davis Institute for Medical Research and McGill University AIDS Center, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E8, Canada
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Michael A. Parniak
Lady Davis Institute for Medical Research and McGill University AIDS Center, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E8, Canada
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  • For correspondence: parniakm@msx.dept-med.pitt.edu
DOI: 10.1128/AAC.46.6.1851-1856.2002
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    FIG. 1.

    Structures of the NNRTI used in the present studies: CSIC (1); DLV (2); EFV (3); NVP (4); UC781 (5); UC84 (6).

  • FIG. 2.
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    FIG. 2.

    Inactivation of isolated HIV-1 virus particles following exposure to different concentrations of NNRTI. Isolated HIV-1 particles were incubated with the indicated concentrations of various NNRTI for 2 h at 37°C. Excess drug was then removed by repeated dilution and concentration steps, as described in Materials and Methods. The exogenous drug-free virus was then used to infect MT-2 lymphocytes, and the extents of HIV-1-induced cytopathic effects were assessed 4 days postinfection. ▴, CSIC; ○, EFV; ▪, UC781; □, DLV; ▾, NVP; ▵, UC84. Data points are the means ± standard deviations of three separate determinations.

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    FIG. 3.

    Effects of NNRTI treatment of chronically infected H9+ cells on infectivity of HIV-1 virions subsequently produced in the absence of extracellular drug. H9+ cells were incubated with 20 μM of the indicated NNRTI for 18 h at 37°C, and then the cells were washed free of exogenous drug. The H9+ cells were then cultured for 24 h in the absence of drug, and the virus produced during that period was separated from the cells by centrifugation, as described in Materials and Methods. Equal amounts of virus, corresponding to 0.25 ng of p24, were added to 5 × 104 MT2 cells in a total volume of 200 μl, and the extent of infection of these cells was determined after 4 days by microscopic evaluation of syncytium formation. The data presented are the means ± standard deviations of three separate determinations.

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    FIG. 4.

    Effects of NNRTI treatment of chronically infected H9+ cells on subsequent cell-to-cell transmission of HIV-1 in the absence of extracellular drug. H9+ chronically infected cells were incubated with the indicated concentrations of CSIC (▴), EFV (▪), UC781 (○), or DLV (□) for 18 h at 37°C, and then the cells were separated from extracellular drug and virus as described in Materials and Methods. The isolated H9+ cells were then cocultured with uninfected MT2 cells (1:300 ratio of H9+ to MT2 cells), and the extent of infection of the latter was determined 4 days later by microscopic assessment of HIV-1-induced syncytium formation.

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    FIG. 5.

    Effects of pretreatment of uninfected MT2 cells with various concentrations of NNRTI on their subsequent infection by HIV-1 in the absence of extracellular drug. Uninfected MT2 cells were incubated with the indicated concentrations of NNRTI for 18 h and then washed to remove exogenous drug. The cells were then exposed to identical inocula of HIV-1 (MOI, 7.5 × 10−3). HIV-1-induced cytopathic effects were assessed daily by microscopic examination of syncytium formation as described in Materials and Methods. (A) CSIC; (B) EFV; (C) UC781; (D) DLV.

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    FIG. 6.

    Effects of viral load on infection of MT2 cells pretreated with various concentrations of tight-binding NNRTI. Uninfected MT2 cells were incubated with the indicated concentrations of NNRTI for 18 h and then washed to remove exogenous drug. The cells were then inoculated with the indicated amounts of HIV-1 (MOI, 0.0007 to 0.18). HIV-1-induced cytopathic effects were assessed 4 days postinfection by microscopic examination of syncytium formation as described in Materials and Methods. (A) CSIC; (B) EFV; (C) UC781.

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  • TABLE 1.

    Some properties of the NNRTI used in this study

    DrugIC50 (nM)aEC50 (nM)bType of inhibitionc
    Clinical
        Nevirapine200 ± 4545 ± 10REI
        Delavirdine5.4 ± 0.42.8 ± 1.4REI
        Efavirenz7.7 ± 0.91.7 ± 0.2TBI
    Experimental
        UC84117 ± 4240 ± 70REI
        UC7811.7 ± 1.210 ± 0.2TBI
        CSIC2.0 ± 0.21.2 ± 0.4TBI
    • ↵ a IC50 is the concentration of inhibitor that provides a 50% reduction in the RDDP activity of recombinant wild-type p51/p66 RT determined by measurement of this activity in the presence of various concentrations of inhibitor using [3H]dGTP and poly(rC)-oligo(dG)12-18 as described in Materials and Methods. Values are the means ± standard deviations of three independent measurements, each carried out in duplicate.

    • ↵ b EC50 is the concentration of inhibitor that provides a 50% reduction in HIV-1 infection of MT2 cells, assessed as described in Materials and Methods. Values are the means ± standard deviations of three independent measurements, each carried out in triplicate.

    • ↵ c Inhibition of HIV-1 RT in vitro: REI, rapid equilibrium inhibitor; TBI, tight-binding inhibitor.

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A Tight-Binding Mode of Inhibition Is Essential for Anti-Human Immunodeficiency Virus Type 1 Virucidal Activity of Nonnucleoside Reverse Transcriptase Inhibitors
Dimitrios Motakis, Michael A. Parniak
Antimicrobial Agents and Chemotherapy Jun 2002, 46 (6) 1851-1856; DOI: 10.1128/AAC.46.6.1851-1856.2002

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A Tight-Binding Mode of Inhibition Is Essential for Anti-Human Immunodeficiency Virus Type 1 Virucidal Activity of Nonnucleoside Reverse Transcriptase Inhibitors
Dimitrios Motakis, Michael A. Parniak
Antimicrobial Agents and Chemotherapy Jun 2002, 46 (6) 1851-1856; DOI: 10.1128/AAC.46.6.1851-1856.2002
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KEYWORDS

Anti-HIV Agents
HIV-1
Reverse Transcriptase Inhibitors

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