4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

POTENT ALKYLGLYCEROL FOSCARNET PRODRUGS INHIBIT NUCLEOSIDE ANALOGUE-RESISTANT HIV-1 AND SELECT FOR MUTATIONS IN RT THAT REVERSE ZIDOVUDINE RESISTANCE

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):4 (Abstract 3

J Hammond¹, D Koontz¹, H Bazmi¹, J Beadle², S Hostetler², G Kini², K Aldern², D Richman², K Hostetler² and J Mellors^1
1VA Medical Centre and University of Pittsburgh, Pa., USA; and ²VA Medical Center and University of California, San Diego, La Jolla, Calif., USA

Although a potent inhibitor of HIV-1 reverse transcriptase, phosphonoformate (PFA, foscarnet) is not used to treat HIV-1 infection because of toxicity and lack of oral bioavailability. Batyl alcohol analogues of PFA (1-O-octadecylglycerol-3-PFA; B-PFA) having sn2 substitutions of hydrogen (deoxybatyl-PFA; DB-PFA), methyl (MB-PFA) or ethyl (EB-PFA) are potent inhibitors of wild-type HIV-1 in vitro and are orally bioavailable in rats. We have now evaluated the activity of these compounds against a panel of nucleoside- resistant HIV-1 variants and have characterized the resistant variants that emerge with in vitro selection. Except for a variant encoding K65R that exhibited 3.3- to 8.2-fold resistance, the nucleoside-resistant viruses were sensitive (<three-fold increase in EC₅₀) to the PFA prodrugs, including a multinucleoside-resistant variant (EC₅₀<1.0 μM). Viruses resistant to the PFA prodrugs were selected in vitro by serial passage of HIV-1 in MT-2 cells in escalating drug concentrations. Virus resistant (>10-fold) to each of the compounds was isolated after ≥15 passages. The following mutations were detected in the resistant viruses: S117T and L214F (DB-PFA); M164I and L214F (MB-PFA); W88G and L214F (EB-PFA); and W88G or S117T (unconjugated PFA). The S117T and M164I mutations have not been previously reported. Generation of recombinant viruses encoding the single and double mutations confirmed their role in prodrug resistance, including 214F, which generally increased the level of prodrug resistance. Recombinant viruses containing W88G/L214F or M164I/L214F displayed hypersensitivity to zidovudine. When introduced into a zidovudine-resistant background (67N, 70R, 215F, 219Q), the W88G, S117T and M164I mutations reversed zidovudine resistance. This reversal of zidovudine resistance is consistent with the effects of other foscarnet resistance mutations that reduce ATP-dependent removal of zidovudine monophosphate from terminated template primers. The favourable activity and resistance profiles of these PFA prodrugs warrant their further evaluation as clinical candidates.

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2000-06-12
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