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Antimicrobial Agents and Chemotherapy, November 1999, p. 2629-2634, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Kinetics of Antiviral Activity and Intracellular Pharmacokinetics of Human Immunodeficiency Virus Type 1 Protease Inhibitors in Tissue Culture

Michelina Nascimbeni,1 Claire Lamotte,2 Gilles Peytavin,2 Robert Farinotti,2 and François Clavel1,*

Laboratoire de Recherche Antivirale, IMEA-INSERM,1 and Laboratoire de Pharmacologie,2 Hôpital Bichat-Claude Bernard, Paris, France

Received 3 February 1999/Returned for modification 23 May 1999/Accepted 30 August 1999

We have examined the kinetics of the inhibition of human immunodeficiency virus type 1 (HIV-1) particle infectivity by protease inhibitors (PIs) in cell culture, using either transfected HeLa cells or infected peripheral blood mononuclear cells (PBMCs) as producers of infectious virions. Both the kinetics of the initiation of antiviral activity after addition of the PIs to these cultures and the kinetics of restoration of virion infectivity after removal of the PIs from the treated cultures were examined. We found that the kinetics of initiation of particle infectivity inhibition produced by a high extracellular concentration (5 µM) of the inhibitors were similar for all five inhibitors tested: loss of particle infectivity was perceptible as early as 1 h after the initiation of PI treatment and increased gradually thereafter. By contrast, the durability of this antiviral effect following removal of the drug from the culture varied dramatically according to the drug studied. In transfected HeLa cells, saquinavir and nelfinavir exerted the most prolonged inhibition, with the half-lives of their antiviral activities being greater than 24 h, while ritonavir exerted an intermediate length of inhibition (18 h) and indinavir and amprenavir exerted a reproducibly shorter length of inhibition (5 h). For all five tested PIs, these kinetics were significantly faster in PBMCs than in HeLa cells. The striking differences in antiviral kinetics observed among the different PIs appear mostly due to differences in their intracellular concentrations and/or rates of cellular clearance. Our observations, although limited to tissue culture conditions, may help delineate the cellular parameters of the antiviral activities of HIV-1 PIs and further optimize the efficiencies of these antiretrovirals in vivo.

* Corresponding author. Mailing address: Laboratoire de Recherche Antivirale, IMEA/INSERM, Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard, 75018 Paris, France. Phone: 331 4025 6363. Fax: 331 4025 8780. E-mail: clavel{at}bichat.inserm.fr.

Antimicrobial Agents and Chemotherapy, November 1999, p. 2629-2634, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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