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Antimicrobial Agents and Chemotherapy, June 2002, p. 1851-1856, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1851-1856.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Dimitrios Motakis and 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

Received 15 August 2001/ Returned for modification 19 November 2001/ Accepted 21 March 2002

It was previously found that certain nonnucleoside reverse transcriptase inhibitors (NNRTI) possess virucidal activity against human immunodeficiency virus type 1 (HIV-1), and it was suggested that the tight-binding mode of inhibition of reverse transcriptase might be important for this virucidal activity (Borkow et al., J. Virol. 71:3023-3030, 1997). To test this, we compared six different NNRTI, including three tight-binding NNRTI, namely UC781, efavirenz (EFV) (Sustiva), and 5-chloro-3-phenylsulfonylindole-2-carboxamide (CSIC), and three rapid-equilibrium NNRTI, delavirdine (DLV) (Rescriptor), nevirapine (NVP) (Viramune), and UC84, in a variety of virucidal tests. Incubation of isolated HIV-1 virions with UC781, EFV, or CSIC rapidly inactivated the virus, whereas DLV, NVP, and UC84 were ineffective in this respect. Exposure of H9+ cells chronically infected by HIV-1 to the tight-binding NNRTI abolished the infectivity of nascent virus subsequently produced by these cells following removal of extracellular drug, thereby preventing cell-to-cell virus transmission in the absence of exogenous drug. In contrast, cell-to-cell transmission of HIV was blocked by DLV, NVP, and UC84 only when the drug remained in the extracellular medium. Pretreatment of uninfected lymphocytoid cells with UC781, EFV, or CSIC, but not DLV, NVP, or UC84, protected these cells from subsequent HIV-1 infection in the absence of extracellular drug. The protective effect was dependent on both the dose of NNRTI and the viral load. The overall virucidal efficacy of the tight-binding NNRTI tested was CSIC > UC781 ~= EFV. We conclude that the tight-binding mode of inhibition is an essential characteristic for virucidal NNRTI and that antiviral potency is an insufficient predictor for virucidal utility of NNRTI.

* Corresponding author. Present address: Division of Infectious Diseases, University of Pittsburgh, Scaife Hall, Room S818D, 3550 Terrace St., Pittsburgh, PA 15261. Phone: (412) 648-1927. Fax: (412) 340-7502. E-mail: parniakm{at}msx.dept-med.pitt.edu.

Antimicrobial Agents and Chemotherapy, June 2002, p. 1851-1856, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1851-1856.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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