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Antimicrobial Agents and Chemotherapy, June 2001, p. 1621-1628, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1621-1628.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Alkylglycerol Prodrugs of Phosphonoformate Are Potent In Vitro Inhibitors of Nucleoside-Resistant Human Immunodeficiency Virus Type 1 and Select for Resistance Mutations That Suppress Zidovudine Resistance

Jennifer L. Hammond,1 Dianna L. Koontz,1 Holly Z. Bazmi,1 James R. Beadle,2 Saskia E. Hostetler,2 Ganesh D. Kini,2 Kathy A. Aldern,2 Douglas D. Richman,2 Karl Y. Hostetler,2 and John W. Mellors1,*

Departments of Medicine and Infectious Diseases and Microbiology, University of Pittsburgh and Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15261,1 and Departments of Medicine and Pathology, Veterans Affairs Medical Center and the University of California, San Diego, La Jolla, California 920932

Received 26 October 2000/Returned for modification 29 January 2001/Accepted 8 March 2001

Phosphonoformate (foscarnet; PFA) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), but its use for the treatment of HIV-1 infection is limited by toxicity and the lack of an orally bioavailable formulation. Alkylglycerol-conjugated prodrugs of PFA (1-O-octadecyl-sn-glycero-3-PFA [B-PFA]) having sn-2 substituents of hydrogen (deoxybatyl-PFA [DB-PFA]), methyl (MB-PFA), or ethyl (EB-PFA) are more-potent inhibitors of wild-type HIV-1 in vitro than unmodified PFA and are orally bioavailable in mice. We have evaluated the activities of these compounds against a panel of nucleoside-resistant HIV-1 variants and have characterized the resistant variants that emerge following in vitro selection with the prodrugs. Except for an HIV-1 variant encoding the K65R mutation in RT that exhibited 3.3- to 8.2-fold resistance, the nucleoside-resistant viruses included in the panel were sensitive to the PFA prodrugs (<3-fold increase in 50% inhibitory concentration), including multinucleoside-resistant variants encoding the Q151M complex of mutations or the T69S[SA] insert. Viruses resistant to the PFA prodrugs (>10-fold) were selected in vitro after 15 or more serial passages of HIV-1 in MT-2 cells in escalating prodrug concentrations. Mutations detected in the resistant viruses were S117T, F160Y, and L214F (DB-PFA); M164I and L214F (MB-PFA); and W88G and L214F (EB-PFA). The S117T, F160Y, and M164I mutations have not been previously identified. Generation of recombinant viruses encoding the single and double mutations confirmed their roles in prodrug resistance, including 214F, which generally increased the level of resistance. When introduced into a zidovudine (AZT)-resistant background (67N 70R 215F 219Q), the W88G, S117T, F160Y, and M164I mutations reversed AZT resistance. This suppression of AZT resistance is consistent with the effects of other foscarnet resistance mutations that reduce ATP-dependent removal of AZT monophosphate from terminated template primers. The favorable activity and resistance profiles of these PFA prodrugs warrant their further evaluation as clinical candidates.

* Corresponding author. Mailing address: 818 Scaife Hall, School of Medicine, University of Pittsburgh, 3550 Terrace St., Pittsburgh, PA 15261. Phone: (412) 624-8512. Fax: (412) 383-7982. E-mail: mellors{at}msx.dept-med.pitt.edu.

Antimicrobial Agents and Chemotherapy, June 2001, p. 1621-1628, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1621-1628.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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