title: Maraviroc treatment in non-R5-HIV-1-infected patients results in the selection of extreme CXCR4-using variants with limited effect on the total viral setpoint.
abstract: OBJECTIVE
  Using deep sequencing methods, we intensively investigated the selective pressure of maraviroc on the viral population in four patients with dual/mixed HIV-1 experiencing treatment failure.
  
  
  METHODS
  Patients received maraviroc add-on therapy (n = 4). Tropism was determined by Monogram's Trofile assay and/or 'deep' sequencing. Longitudinal 'deep' sequence analysis used triplicate HIV V3 RT-PCR on plasma samples. Sequences were interpreted using the geno2phenocoreceptor algorithm with a 3.5% false-positive rate (FPR) cut-off.
  
  
  RESULTS
  Patients had a median viral load of 4.7 log10 HIV RNA copies/mL with a median of 24% chemokine (C-X-C motif) receptor 4 (CXCR4)-using virus at baseline. Following maraviroc exposure, the chemokine (C-C motif) receptor 5 (CCR5)-using virus (R5) plasma viral load decreased by at least 1 log10, and only non-R5 variants with extremely low FPR values predominated after 21 days. Virus with an FPR ≤1.8% accounted for more than 90% of the circulating virus, having expanded to occupy the 'space' left by the suppression of R5 variants. Population genetic estimates of viral fitness in the presence of maraviroc showed a steep rise around an FPR value of 2%.
  
  
  CONCLUSIONS
  Longitudinal analysis of independent R5 and non-R5 HIV populations shows that maraviroc selects viruses with an extremely low FPR, implying that the antiviral activity of maraviroc may extend to a broader range of HIV variants than previously suspected.
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada V6Z 1Y6.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: McGovern
authors.forename: Jori
authors.initials: J
authors.lastname: Symons
authors.forename: Art F Y
authors.initials: AF
authors.lastname: Poon
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.forename: Steven F L
authors.initials: SF
authors.lastname: van Lelyveld
authors.forename: Andy I M
authors.initials: AI
authors.lastname: Hoepelman
authors.forename: Petra M
authors.initials: PM
authors.lastname: van Ham
authors.forename: Winnie
authors.initials: W
authors.lastname: Dong
authors.forename: Annemarie M J
authors.initials: AM
authors.lastname: Wensing
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D003510:Cyclohexanes / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008137:Longitudinal Studies; D000077592:Maraviroc; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015728:Receptors, HIV / Q000378:metabolism; D012641:Selection, Genetic; D014230:Triazoles / Q000627:therapeutic use*; D056189:Viral Tropism
chemical_list: D019380:Anti-HIV Agents; C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D003510:Cyclohexanes; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV; D014230:Triazoles; D000077592:Maraviroc
keywords: 454 deep sequencing; V3 loop; dual/mixed tropism; genotyping