Long-Term Foscarnet Therapy Remodels Thymidine Analogue Mutations and Alters Resistance to Zidovudine and Lamivudine in HIV-1

• DOI: 10.1177/135965350701200310
• Publication Date: 2022-04-14T16:01:46Z
• Authors: Sofie Mathiesen; Elisabeth Dam; Birgit Roge; Louise Bruun Joer...; Alex Lund Laursen; Jan Gerstoft; Francois Clavel
• Keywords: Resistance mutation; Reversion; clone (Java method)

Objective To study the evolution of multi-drug-resistant HIV-1 in treatment-experienced patients receiving foscarnet (PFA) as part salvage therapy and to investigate virological consequences emerging mutations. Methods Genotypic phenotypic resistance tests were performed on plasma viruses from seven at baseline during treatment with PFA. The effects mutations suspected be associated PFA evaluated by site-directed mutagenesis wild-type or thymidine analogue (TAM)-carrying pNL4–3. Reversion single was a patient-derived recombinant clone. Results Baseline isolates exhibited hypersusceptibility In two who received >12 months treatment, novel mutation pattern including K70G, V75T, K219R L228R emerged. These had 3–6-fold PFA, 2–20-fold decrease zidovudine compared baseline, 14–39-fold lamivudine, absence M184V. clones K70G V75T induced moderate resistance. case TAMs, combinations ≥3 (K70G+K219R+L228R±V75T) decreased 3–13-fold. mutants high-level lamivudine (>20-fold) without K70G→R K219R→E clone confirmed contribution individual negative association between Conclusions context multiple observed resistance, alternative amino acid substitutions TAM loci, This mutational decreases surprisingly