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Anti-HIV-1 Activity of 3'-Fluoro-3'-deoxythymidine for Different Multidrug-Resistant Mutants E.-Y. KIM*1, L. VRANG2, B. OBERG2, and T. C. MERIGAN1.
1Stanford Univ., Ctr. for AIDS Res., CA; and 2Medivir AB, Huddinge, Sweden Objective: To test the antiviral activity of a potent nucleoside reverse transcriptase inhibitor, 3'-fluoro-3'deoxythymdine (FLT), on both a wild-type human immunodeficiency virus (HIV-1) isolate and multi-drug resistant HIV-1 patient isolates.
Methods: Drug resistant viral isolates were selected based on the four different categories of significant mutants. The isolates included three multidrug resistant viruses containing 151M alone or in combination, three resistant viruses containing 215Y and 41L, 67N, 184V, 210W, 219N in combination, two insertion mutant viruses (69+EA and 69+SA), and two deletion mutant viruses (del67NG and del67GS), the latter two groups both containing other significant mutations. The activity of FLT against these isolates was determined using drug susceptibility assays and measuring the viral antigen p24 by ELISA. The cytotoxicity of FLT and AZT was assessed in PHA-stimulated PBMCs. The development of resistant mutants under the FLT pressure was undertaken by passaging HIV-1 isolates in SupT1 and MT-4 cells and stepwise increasing the concentration of the FLT.
Results: The multidrug resistant mutant HIV-1 isolates exhibited 5-fold to >100-fold increased resistance to AZT, but showed IC50 values for FLT of 0.0014-0.0162mM which are lower than or similar to that of wild type(0.0075mM). The cellular cytotoxicities of FLT and AZT fell into a similar range in PBMCs. The development of resistant mutant HIV isolates to FLT appears slower than for other RT inhibitors.
Conclusion: Virus isolates with significant mutations had no evidence of resistance to FLT. FLT and AZT are thymidine analogs modified solely in the 3' position where the OH group is changed to fluoro and azido, respectively. The fluoro atom size is more similar than azido to the OH group. This structural characteristic of FLT is more likely to be accepted by reverse transcriptases with multidrug resistance. FLT may be useful in salvage therapies for patients harboring resistant strains.
Key Words: FLT, HIV-1 RT inhibitor, Multidrug Resistance
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