Tenofovir resistance and resensitization.
Human immunodeficiency viruses in 321 samples from tenofovir-naïve 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 < 0.001). Among the viruses in the clinical samples, the rate of tenofovir resistance significantly increased with the number of TAMs both in the samples with 184M and in those with 184V (P = 0.005 and P = 0.003, respectively). A resensitizing effect of M184V was confirmed for all samples exhibiting at least one TAM (P = 0.03). However, accumulation of at least two TAMs resulted in more than 2.0-fold reduced susceptibility to tenofovir, irrespective of the presence of M184V. Decision tree building, a classical machine learning technique, was used to generate models for the interpretation of mutations with respect to tenofovir resistance. The application of previously proposed cutoffs for a reduced response to therapy and treatment failure demonstrated the central roles of positions 215 and 65 for 1.5- and 4.0-fold reduced susceptibilities, respectively. Thus, clinically relevant resistance may be conferred by the accumulation of TAMs, and the resensitizing effect of M184V should be considered only minor.
Institute of Clinical and Molecular Virology, German National Reference Centre for Retroviruses, University of Erlangen-Nuremberg, Erlangen, Germany.
Katharina
K
Wolf
Hauke
H
Walter
Niko
N
Beerenwinkel
Wilco
W
Keulen
Rolf
R
Kaiser
Daniel
D
Hoffmann
Thomas
T
Lengauer
Joachim
J
Selbig
Anne-Mieke
AM
Vandamme
Klaus
K
Korn
Barbara
B
Schmidt
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019295:Computational Biology; D024882:Drug Resistance, Viral; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D000068698:Tenofovir; D013936:Thymidine / Q000031:analogs & derivatives / Q000235:genetics
D063065:Organophosphonates; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine; D013936:Thymidine