title: Infection with the frequently transmitted HIV-1 M41L variant has no influence on selection of tenofovir resistance.
abstract: OBJECTIVE
  In ∼10% of newly diagnosed HIV-1 patients, drug-resistant viral variants are detected. In such transmitted HIV-1 variants, the thymidine analogue mutation (TAM) M41L is frequently observed as a single resistance mutation and these viral variants often belong to phylogenetic transmission clusters. The presence of at least three TAMs, in particular patterns with M41L/L210W, impairs the efficacy of the extensively used drug tenofovir. We investigated whether the presence of a single M41L mutation at baseline influences the selection of resistance to tenofovir and emtricitabine in vitro and in vivo.
  
  
  METHODS
  The impact of M41L on the development of drug resistance to tenofovir and emtricitabine was determined by extensive in vitro selection experiments and investigation of the virological outcome of patients on a first-line regimen.
  
  
  RESULTS
  The presence of a single M41L mutation did not influence the selected mutational profile or the genetic barrier to resistance to tenofovir and/or emtricitabine during long-term in vitro selection experiments. In vivo, virological outcome of first-line regimens containing tenofovir and emtricitabine was comparable between patients diagnosed with HIV-1 harbouring M41L (n=17, 16 were part of one transmission cluster) and WT virus (n=248).
  
  
  CONCLUSIONS
  Detection of a single M41L reverse transcriptase mutation at baseline did not influence the development of resistance in vitro or virological outcome on tenofovir-containing regimens in patients belonging to a large transmission cluster. Our results indicate that a high genetic barrier regimen may not be required when patients are diagnosed with HIV variants containing a single M41L mutation in reverse transcriptase.
authors.affiliation: Virology, Department of Medical Microbiology, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Department of Virology, Erasmus MC, University Medical Center, Dr. Watermolenplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Pingen
authors.affiliation: Virology, Department of Medical Microbiology, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
authors.affiliation: Department of Internal Medicine and Infectious Diseases, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Tania
authors.initials: T
authors.lastname: Mudrikova
authors.affiliation: Virology, Department of Medical Microbiology, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Department of Internal Medicine and Infectious Diseases, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Arjan
authors.initials: A
authors.lastname: van Laarhoven
authors.affiliation: Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6815 AD Arnhem, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: Langebeek
authors.affiliation: Department of Internal Medicine, Rijnstate Hospital, Wagnerlaan 55, 6815 AD Arnhem, The Netherlands.
authors.forename: Clemens
authors.initials: C
authors.lastname: Richter
authors.affiliation: Department of Virology, Erasmus MC, University Medical Center, Dr. Watermolenplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: Charles A B
authors.initials: CA
authors.lastname: Boucher
authors.affiliation: Virology, Department of Medical Microbiology, UMC Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands a.m.j.wensing@umcutrecht.nl.
authors.forename: Annemarie M J
authors.initials: AM
authors.lastname: Wensing
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D019943:Amino Acid Substitution; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D000068679:Emtricitabine; D019143:Evolution, Molecular; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000145:classification / Q000235:genetics*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D010802:Phylogeny; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000068698:Tenofovir; D019562:Viral Load
chemical_list: D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000068679:Emtricitabine; D000225:Adenine
keywords: Atripla®; Truvada®; drug resistance; emtricitabine; transmission