title: E17A mutation in HIV-1 Vpr confers resistance to didanosine in association with thymidine analog mutations.
abstract: BACKGROUND
  HIV-1 accessory Vpr protein is involved in the reverse transcription process and has been shown to modulate the virus mutation rate. This process may play a role in the kinetics of appearance of drug resistance mutations under antiretroviral treatment.
  
  
  METHODS
  Vpr sequences were analyzed from plasma viruses derived from 97 HIV-1-infected individuals failing antiretroviral treatment and 63 antiretroviral-naïve patients. Vpr genetic variability was analyzed for association with specific drug treatment and drug resistance mutations. Biological and virological experiments were employed to characterize a mutation in Vpr found to be associated with virological failure.
  
  
  RESULTS
  E17A mutation located in the first α-helix of Vpr was more prevalent in HAART-treated individuals compared to untreated individuals. E17A was associated with thymidine analog mutations (TAMs) in reverse transcriptase M41L, L210W and T215Y and with the use of didanosine in the patients' treatment histories. E17A had no impact on the biochemical and functional properties of Vpr, and did not affect kinetics of replication of wild-type or TAMs-containing viruses. However, its association with TAMs and the use of didanosine was consistent with phenotypic susceptibility assays showing a significant 3-fold decrease in didanosine susceptibility of viruses harboring Vpr E17A combined with TAMs compared to viruses harboring TAMs alone.
  
  
  CONCLUSIONS
  These findings highlight a novel role of Vpr in HIV-1 drug resistance. Vpr E17A confers resistance to didanosine when associated with TAMs. Whether Vpr E17A facilitates excision of didanosine is still to be determined.
authors.affiliation: Université Pierre et Marie Curie, Paris, France. slim.fourati@psl.aphp.fr
authors.forename: Slim
authors.initials: S
authors.lastname: Fourati
authors.forename: Isabelle
authors.initials: I
authors.lastname: Malet
authors.forename: Carolin A
authors.initials: CA
authors.lastname: Guenzel
authors.forename: Cathia
authors.initials: C
authors.lastname: Soulie
authors.forename: Priscilla
authors.initials: P
authors.lastname: Maidou-Peindara
authors.forename: Laurence
authors.initials: L
authors.lastname: Morand-Joubert
authors.forename: Marc
authors.initials: M
authors.lastname: Wirden
authors.forename: Sophie
authors.initials: S
authors.lastname: Sayon
authors.forename: Gilles
authors.initials: G
authors.lastname: Peytavin
authors.forename: Anne
authors.initials: A
authors.lastname: Simon
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Serge
authors.initials: S
authors.lastname: Benichou
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
authors.forename: Anne-Geneviève
authors.initials: AG
authors.lastname: Marcelin
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016049:Didanosine / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D016334:Genes, vpr; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D021381:Protein Transport; D013936:Thymidine / Q000031:analogs & derivatives / Q000235:genetics; D014779:Virus Replication / Q000235:genetics; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D019380:Anti-HIV Agents; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D016049:Didanosine; D013936:Thymidine