title: Epidemiological and biological evidence for a compensatory effect of connection domain mutation N348I on M184V in HIV-1 reverse transcriptase.
abstract: BACKGROUND
  The connection domain mutation N348I confers resistance to zidovudine (AZT) and is associated with the lamivudine (3TC) mutation M184V. We explored the biochemical and virological influence of N348I in the context of M184V.
  
  
  METHODS
  Genotypic resistance data for patients receiving monotherapy or dual therapy with AZT, lamivudine (3TC), or AZT/3TC were analyzed. Rates of N348I emergence were compared between treatment groups. Mutant reverse transcriptases (RTs) containing M184V and/or N348I were generated to study enzymatic and virological properties.
  
  
  RESULTS
  We included 50 AZT-treated, 11 3TC-treated, and 10 AZT/3TC-treated patients. N348I was observed in 3 (6%), 0, and 4 (40%) of these patients, respectively. The rate of N348I emergence was increased by 5-fold in the AZT/3TC group (11.7 instances [95% confidence interval {CI}, 3.2-30.1 instances] per 100 person-years of receipt of AZT), compared with the rate noted for the AZT group (2.3 instances [95% CI, 0.4-6.8 instances] per 100 person-years of receipt of AZT; P = .04). Biochemical data show that N348I can partially compensate for the diminution in processive DNA synthesis and the reduction in AZT excision associated with M184V. Furthermore, virological analyses demonstrate that N348I confers low-level resistance to AZT and partly restores the reduced RT activity of the M184V variant.
  
  
  CONCLUSIONS
  In vivo selection of N348I is driven by AZT and is further facilitated when 3TC is coadministered. Compensatory interactions between N348I and M184V help to explain these findings.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 8091 Zurich, Switzerland. huldrych.guenthard@usz.ch
authors.forename: Viktor
authors.initials: V
authors.lastname: von Wyl
authors.forename: Maryam
authors.initials: M
authors.lastname: Ehteshami
authors.forename: Jori
authors.initials: J
authors.lastname: Symons
authors.forename: Philippe
authors.initials: P
authors.lastname: Bürgisser
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Demeter
authors.forename: Sabine
authors.initials: S
authors.lastname: Yerly
authors.forename: Jürg
authors.initials: J
authors.lastname: Böni
authors.forename: Thomas
authors.initials: T
authors.lastname: Klimkait
authors.forename: Rob
authors.initials: R
authors.lastname: Schuurman
authors.forename: Bruno
authors.initials: B
authors.lastname: Ledergerber
authors.forename: Matthias
authors.initials: M
authors.lastname: Götte
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
mesh_terms: D002460:Cell Line; D004279:DNA, Viral; D024921:Drug Resistance, Multiple, Viral; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D054309:Ribonuclease H, Human Immunodeficiency Virus; D012641:Selection, Genetic; D018709:Statistics, Nonparametric; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D054309:Ribonuclease H, Human Immunodeficiency Virus