TY - JOUR
T1 - Long-term foscarnet therapy remodels thymidine analogue mutations and alters resistance to zidovudine and lamivudine in HIV-1
AU - Mathiesen, Sofie
AU - Dam, Elisabeth
AU - Roge, Birgit
AU - Joergensen, Louise Bruun
AU - Laursen, Alex Lund
AU - Gerstoft, Jan
AU - Clavel, Francois
PY - 2007
Y1 - 2007
N2 - OBJECTIVE: To study the evolution of multi-drug-resistant HIV-1 in treatment-experienced patients receiving foscarnet (PFA) as part of salvage therapy and to investigate the virological consequences of emerging mutations.METHODS: Genotypic and phenotypic resistance tests were performed on plasma viruses from seven patients at baseline and during treatment with PFA. The phenotypic effects of mutations suspected to be associated with PFA resistance were evaluated by site-directed mutagenesis of wild-type or thymidine analogue mutations (TAM)-carrying pNL4-3. Reversion of single mutations was performed in a patient-derived recombinant clone.RESULTS: Baseline multi-drug-resistant isolates exhibited hypersusceptibility to PFA. In two patients who received > 12 months of PFA treatment, a novel mutation pattern including K70G, V75T, K219R and L228R emerged. These viruses had 3-6-fold resistance to PFA, a 2-20-fold decrease in resistance to zidovudine compared to baseline, and 14-39-fold resistance to lamivudine, in the absence of M184V. In wild-type clones mutations K70G and V75T induced moderate PFA resistance. In the case of TAMs, combinations of > or = 3 mutations (K70G+K219R+L228R+/-V75T) induced PFA resistance and decreased zidovudine resistance 3-13-fold. These mutants exhibited high-level lamivudine resistance (>20-fold) without mutation M184V. Reversion of K70G --> R and K219R --> E in a patient-derived clone confirmed the contribution of individual mutations and the negative association between PFA resistance and zidovudine resistance.CONCLUSIONS: In the context of multiple TAMs, hypersusceptibility to PFA was observed and a novel pattern of resistance, including alternative amino acid substitutions at TAM loci, emerged. This mutational pattern was associated with decreases in zidovudine resistance and surprisingly high-level lamivudine resistance.
AB - OBJECTIVE: To study the evolution of multi-drug-resistant HIV-1 in treatment-experienced patients receiving foscarnet (PFA) as part of salvage therapy and to investigate the virological consequences of emerging mutations.METHODS: Genotypic and phenotypic resistance tests were performed on plasma viruses from seven patients at baseline and during treatment with PFA. The phenotypic effects of mutations suspected to be associated with PFA resistance were evaluated by site-directed mutagenesis of wild-type or thymidine analogue mutations (TAM)-carrying pNL4-3. Reversion of single mutations was performed in a patient-derived recombinant clone.RESULTS: Baseline multi-drug-resistant isolates exhibited hypersusceptibility to PFA. In two patients who received > 12 months of PFA treatment, a novel mutation pattern including K70G, V75T, K219R and L228R emerged. These viruses had 3-6-fold resistance to PFA, a 2-20-fold decrease in resistance to zidovudine compared to baseline, and 14-39-fold resistance to lamivudine, in the absence of M184V. In wild-type clones mutations K70G and V75T induced moderate PFA resistance. In the case of TAMs, combinations of > or = 3 mutations (K70G+K219R+L228R+/-V75T) induced PFA resistance and decreased zidovudine resistance 3-13-fold. These mutants exhibited high-level lamivudine resistance (>20-fold) without mutation M184V. Reversion of K70G --> R and K219R --> E in a patient-derived clone confirmed the contribution of individual mutations and the negative association between PFA resistance and zidovudine resistance.CONCLUSIONS: In the context of multiple TAMs, hypersusceptibility to PFA was observed and a novel pattern of resistance, including alternative amino acid substitutions at TAM loci, emerged. This mutational pattern was associated with decreases in zidovudine resistance and surprisingly high-level lamivudine resistance.
KW - Amino Acid Substitution
KW - Anti-HIV Agents/pharmacology
KW - Drug Resistance, Multiple, Viral/genetics
KW - Evolution, Molecular
KW - Foscarnet/pharmacology
KW - HIV Infections/drug therapy
KW - HIV Reverse Transcriptase/genetics
KW - HIV-1/drug effects
KW - Humans
KW - Lamivudine/pharmacology
KW - Microbial Sensitivity Tests
KW - Point Mutation
KW - Reverse Transcriptase Inhibitors/pharmacology
KW - Species Specificity
KW - Thymidine/analogs & derivatives
KW - Time Factors
KW - Zidovudine/pharmacology
M3 - Journal article
C2 - 17591023
SN - 1359-6535
VL - 12
SP - 335
EP - 343
JO - Antiviral Therapy
JF - Antiviral Therapy
IS - 3
ER -