Subtype-specific differences in the development of accessory mutations associated with high-level resistance to hiv-1 nucleoside reverse transcriptase inhibitors

F. A. Koning, H. Castro, D. Dunn, P. Tilston, Patricia Cane, Jean Mbisa

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Objectives: 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

Original languageEnglish
Pages (from-to)1220-1236
Number of pages17
JournalJournal of Antimicrobial Chemotherapy
Volume68
Issue number6
DOIs
Publication statusPublished - Jun 2013

Keywords

  • NNRTIs
  • Subtype B
  • Subtype C
  • Thymidine analogues
  • Viral fitness

Fingerprint

Dive into the research topics of 'Subtype-specific differences in the development of accessory mutations associated with high-level resistance to hiv-1 nucleoside reverse transcriptase inhibitors'. Together they form a unique fingerprint.

Cite this