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

Brenner, Bluma Ga; Oliveira, Maureena; Doualla-Bell, Florencea,b; Moisi, Daniela Da; Ntemgwa, Michela; Frankel, Fernandoa; Essex, Maxb; Wainberg, Mark Aa

doi: 10.1097/01.aids.0000232228.88511.0b
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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 crossresistance 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.

From the aMcGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada

bBotswana-Harvard Laboratory, Gaborone, Botswana.

Received 31 January, 2006

Revised 9 March, 2006

Accepted 13 March, 2006

Correspondence to Mark A. Wainberg, McGill AIDS Centre, Jewish General Hospital, 3755 Cote Ste Catherine Road, Montreal, Quebec, Canada H3T 1E2. Tel: +1 514 340 8260; fax: +1 514 340 7537; e-mail: mark.wainberg@mcgill.ca

© 2006 Lippincott Williams & Wilkins, Inc.