Anti-HIV type 1 activity of 3 '-fluoro-3 '-deoxythymidine for several different multidrug-resistant mutants

The objective of this work was to test the antiviral activity of a potent n ucleoside reverse transcriptase inhibitor, 3'-fluoro-3'-deoxythymidine (FLT ), on both a wild-type human immunodeficiency virus (HIV-1) isolate and mul tidrug-resistant HIV-1 patient isolates. Drug-resistant viral isolates were selected on the basis of four different categories of well-characterized a nd representative multidrug-resistant mutants. The isolates included three variants containing 151M alone or in combination; three variants containing 215Y and 41L, 67N, 184V, 210W, and 219N in combination; two insertion muta nt viruses (69+EA and 69+SA); and two deletion mutant viruses (del67NG and del67GS), the latter two groups both also containing other significant muta tions. The activity of FLT and AZT against these isolates was determined by drug susceptibility assays and by measuring viral antigen p24 by ELISA, Th e cytotoxicity of PLT and AZT was assessed in PHA-stimulated PBMCs. Develop ment of resistant mutants under FLT pressure was attempted by passaging HIV -1 isolates in SupT1 cells and stepwise increasing the concentration of FLT . The multidrug-resistant mutant HIV-1 isolates exhibited 7-fold to >100-fo ld increased resistance to AZT, but showed IC50 values for FLT of 0.0014-0. 0168 muM, which were lower than or similar to that of wild type (0.0075 muM ). The cellular cytotoxicities of FLT and AZT fell into a similar range in PBMCs, The development of HIV mutants resistant to FLT appeared to be slowe r than for other RT inhibitors. HIV isolates with mutations resulting in mu ltidrug resistance had no evidence of resistance to FLT. FLT may be useful in salvage therapies for patients harboring resistant strains and a reasses sment of its therapeutic potential seems required.