HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture

AIDS. 2006 Jun 12;20(9):F9-13. doi: 10.1097/01.aids.0000232228.88511.0b.


Background: Genotypic diversity among HIV-1 subtypes and circulating recombinant forms (CRF) may lead to distinct pathways to drug resistance. This study evaluated subtype-related differences in the development of resistance in culture to tenofovir.

Methods: Genotyping determined nucleotide diversity among subtypes. Representative subtype B, C, CRF1_AE, CRF2_AG, G, and HIV-2 isolates were selected for resistance to tenofovir, lamivudine and didanosine in cell culture. Phenotypic assays determined the effects of the K65R substitution in reverse transcriptase (RT) on drug susceptibility.

Results: Subtype C isolates show unique polymorphisms in RT codons 64 (AAG-->AAA), 65 (AAA-->AAG), and 66 (AAA-->AAG), absent in other subtypes. The K65R mutation (AAG-->AGG) arose with tenofovir by week 12 in four subtype C selections. In contrast, no tenofovir resistance arose in four subtype B (> 34-74 weeks), one each of CRF2_AG and G (> 30-33 weeks), and three HIV-2 (> 27-28 weeks) selections. K65R appeared after 55 and 73 weeks in two CRF1_AE selections with tenofovir. In contrast, times to the appearance of M184V with lamivudine pressure (weeks 8-14) did not vary among subtypes. Selective didanosine pressure resulted in the appearance of M184V and L74V after 38 weeks in two of four subtype C selections. The K65R transitions in subtype C and other subtypes (AGG and AGA) conferred similar 6.5-10-fold resistance to tenofovir and five to 25-fold cross-resistance to each of abacavir, lamivudine, and didanosine, while not affecting zidovudine susceptibility.

Conclusion: Tenofovir -based regimens will need to be carefully monitored in subtype C infections for the possible selection of K65R.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Didanosine
  • Drug Administration Schedule
  • Drug Resistance, Multiple, Viral / genetics*
  • Genetic Variation
  • Genotype
  • HIV-1 / genetics*
  • Humans
  • Inhibitory Concentration 50
  • Lamivudine
  • Microbial Sensitivity Tests
  • Organophosphonates*
  • Polymorphism, Genetic*
  • Reverse Transcriptase Inhibitors*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tenofovir
  • Time Factors


  • Organophosphonates
  • Reverse Transcriptase Inhibitors
  • Lamivudine
  • Tenofovir
  • Adenine
  • Didanosine