title: Subtype-specific differences in the development of accessory mutations associated with high-level resistance to HIV-1 nucleoside reverse transcriptase inhibitors.
abstract: OBJECTIVE
  To identify accessory mutations associated with high-level resistance to reverse transcriptase (RT) inhibitors in HIV-1 subtypes B and C.
  
  
  METHODS
  Changes relative to the wild-type for codons 1-400 of RT were analysed from treatment-experienced patients infected with subtypes B (5464 patients) and C (1920 patients). Positions associated with the accumulation of mutations conferring resistance to thymidine analogues and to non-nucleoside RT inhibitors (NNRTIs) were identified. A subtype-specific single-replication cycle drug susceptibility assay was used to determine whether some of the mutations affected drug susceptibility or viral infectivity.
  
  
  RESULTS
  In subtype B, mutations at 31 and 26 positions were associated with the accumulation of thymidine analogue mutations (TAMs) and NNRTI mutations, respectively; in subtype C, 18 and 13 positions were identified, respectively. Amino acid changes at the following positions were differentially associated with (i) the accumulation of 0-4+ TAMs in subtypes B and C (away from consensus): 43 (27.0% B versus 2.5% C); 118 (36.4% B versus 16.2% C); 135 (12.5% B versus 28.0% C); and 326 (2.6% towards consensus in B versus 7.6% away in C) and (ii) the accumulation of 0-3+ NNRTI mutations (away from consensus): 43 (10.2% B versus 0.5% C); and 68 (5.2% B versus 10.3% C). Codon changes K43E, E44D and V118I were found to have no effect on susceptibility to three NRTIs with or without TAMs in either subtype; however, some accessory mutations had subtype-specific effects on viral infectivity.
  
  
  CONCLUSIONS
  Differences between subtypes B and C were observed in the development and effect of accessory mutations associated with high-level resistance to RT inhibitors.
authors: Antiviral Unit, Virus Reference Department, Health Protection Agency, London, UK.
authors: F A
authors: FA
authors: Koning
authors: H
authors: H
authors: Castro
authors: D
authors: D
authors: Dunn
authors: P
authors: P
authors: Tilston
authors: P A
authors: PA
authors: Cane
authors: J L
authors: JL
authors: Mbisa
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D003062:Codon; D016208:Databases, Factual; D024882:Drug Resistance, Viral / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013045:Species Specificity; D013936:Thymidine / Q000378:metabolism; D006113:United Kingdom; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000596:Amino Acids; D003062:Codon; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D013936:Thymidine
keywords: NNRTIs; subtype B; subtype C; thymidine analogues; viral fitness