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Antimicrobial Agents and Chemotherapy, December 1998, p. 3157-3162, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Human Immunodeficiency Virus Protease Inhibitors Serve as Substrates for Multidrug Transporter Proteins MDR1 and MRP1 but Retain Antiviral Efficacy in Cell Lines Expressing These Transporters

Ranga V. Srinivas,1,* David Middlemas,2 Pat Flynn,1 and Arnold Fridland1

Department of Infectious Diseases1 and Department of Molecular Pharmacology,2 St. Jude Children's Research Hospital, Memphis, Tennessee

Received 26 May 1998/Returned for modification 17 August 1998/Accepted 3 October 1998

The human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs)---saquinavir, ritonavir, nelfinavir, and indinavir---interact with the ABC-type multidrug transporter proteins MDR1 and MRP1 in CEM T-lymphocytic cell lines. Calcein fluorescence was significantly enhanced in MDR1+ CEM/VBL100 and MRP1+ CEM/VM-1-5 cells incubated in the presence of various HIV PIs and calcein acetoxymethyl ester. HIV PIs also enhanced the cytotoxic activity of doxorubicin, a known substrate for MDR1 and MRP1, in both VBL100 and VM-1-5 CEM lines. Saquinavir, ritonavir, and nelfinavir enhanced doxorubicin toxicity in CEM/VBL100 cells by approximately three- to sevenfold. Saquinavir and ritonavir also enhanced doxorubicin toxicity in CEM/VM-1-5 cells. HIV-1 replication was effectively inhibited by the various PIs in all of the cell lines, and the 90% inhibitory concentration for a given compound was comparable between the different cell types. Therefore, overexpression of MDR1 or MRP1 by T lymphocytes is not likely to limit the antiviral efficacy of HIV PI therapy.

* Corresponding author. Mailing address: Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-2359. Fax: (901) 495-3099. E-mail: ranga.srinivas{at}stjude.org.

Antimicrobial Agents and Chemotherapy, December 1998, p. 3157-3162, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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