Tenofovir resistance and resensitization

H Walter, N Beerenwinkel, W Keulen, R Kaiser, D Hoffmann, T Lengauer, J Selbig, AM Vandamme, K Korn, B Schmidt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Human immunodeficiency viruses in 321 samples from tenofovir-naive patients were retrospectively evaluated for resistance to this nucleotide analogue. All virus strains with insertions between amino acids 67 and 70 of the reverse transcriptase (n=6) were highly resistant. Virus strains with the Q151M mutation were divided into susceptible (n=12) and highly resistant (n=8) viruses. This difference was due to the absence or presence of the K65R mutation, which was confirmed by site-directed mutagenesis. Viral clones with various combinations of the mutations M41L, K70R, L210W, and T215F or T215Y were analyzed for cross-resistance induced by thymidine analogue mutations (TAMS). The levels of increased resistance induced by single, double, and triple mutations at the indicated positions could be ranked as follows: for mutants with single mutations, mutations at positions 41>215>70; for mutants with double mutations, mutations at positions 41 and 215>70 and 215=210 and 215>41 and 70; for mutants with triple mutations, mutations at positions 41, 210, and 215>41, 70, and 215. Viral clones with M184V or M184I exhibited slightly increased susceptibilities to tenofovir (0.7-fold). Almost all clones with TAM-induced resistance were resensitized when M184V was present (P

Original languageEnglish
Pages (from-to)3478-3484
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume47
Issue number11
DOIs
Publication statusPublished - Nov-2003

Keywords

  • IMMUNODEFICIENCY-VIRUS TYPE-1
  • REVERSE-TRANSCRIPTASE INHIBITORS
  • ANTIRETROVIRAL-EXPERIENCED PATIENTS
  • DRUG-RESISTANCE
  • VIRAL REPLICATION
  • RHESUS MACAQUES
  • IN-VITRO
  • HIV-1
  • PMPA
  • ZIDOVUDINE

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