title: Early selection of resistance-associated mutations in HIV-1 RT C-terminal domains across different subtypes: role of the genetic barrier to resistance.
abstract: OBJECTIVE
  Interpretation of drug resistance mutation (DRM) has been based solely on HIV-1 subtype B. Reverse transcriptase (RT) C-terminal domains have been disregarded in resistance interpretation, as their clinical relevance is still controversial. We determined the emergence of DRM in RT C-terminal domains of different HIV-1 subtypes, the genetic barrier for the acquisition of these DRM and their temporal appearance with 'classical' RT inhibitor (RTI) mutations.
  
  
  METHODS
  HIV-1 RT sequences were obtained from information from 6087 treatment-naive and 3795 RTI-treated patients deposited in the Stanford HIV Resistance Database, including all major subtypes. DRM emergence was evaluated for subtype B, and was correlated with the number of DRM in the polymerase domain. Genetic barrier was calculated for each DRM studied and in each subtype.
  
  
  RESULTS
  N348I, T369I and A360V were found at low prevalence in treatment-naive isolates of all subtypes. A371V was common to treatment-naive isolates. N348I was observed in all subtypes, while T369I was only selected in subtype C. A360V and T369V were selected by RTI treatment in several subtypes. A371V was selected in subtypes B and C, but is a signature in subtype A. RT C-terminal mutations were correlated with early drug resistance in subtype B. All subtypes have a low calculated genetic barrier towards C-terminal DRM acquisition, despite a few disparities having been observed.
  
  
  CONCLUSIONS
  C-terminal mutations were selected in all HIV-1 subtypes, while some represent subtype-specific signatures. The selection of C-terminal DRMs occurs early in RTI resistance failure in subtype B.
authors.affiliation: Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Cláudia P
authors.initials: CP
authors.lastname: Muniz
authors.affiliation: Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Programa de Genética, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Soares
authors.affiliation: Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil andre20@globo.com.
authors.forename: André F
authors.initials: AF
authors.lastname: Santos
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D012641:Selection, Genetic
chemical_list: D019380:Anti-HIV Agents; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: RNase H; connection; drug resistance; genetic barrier; subtype