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


CONCLUSIONS
Tenofovir -based regimens will need to be carefully monitored in subtype C infections for the possible selection of K65R.
Brenner
Bluma G
BG
McGill University AIDS Centre, Jewish General Hospital, 3755 Côte Ste Catherine Road, Montreal, Quebec, Canada.
Oliveira
Maureen
M
Doualla-Bell
Florence
F
Moisi
Daniela D
DD
Ntemgwa
Michel
M
Frankel
Fernando
F
Essex
Max
M
Wainberg
Mark A
MA
D000225:Adenine / Q000031:analogs & derivatives*; D016049:Didanosine; D004334:Drug Administration Schedule; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D019259:Lamivudine; D008826:Microbial Sensitivity Tests; D063065:Organophosphonates; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068698:Tenofovir; D013997:Time Factors
D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D000068698:Tenofovir; D000225:Adenine; D016049:Didanosine