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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture
AIDS, Volume 20, No. 9, Year 2006
Notification
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Description
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. © 2006 Lippincott Williams & Wilkins.
Authors & Co-Authors
Brenner, Bluma G.
Canada, Montreal
Sir Mortimer B. Davis Jewish General Hospital
Oliveira, Maureen
Canada, Montreal
Sir Mortimer B. Davis Jewish General Hospital
Doualla-Bell, Florence
Canada, Montreal
Sir Mortimer B. Davis Jewish General Hospital
Botswana, Gaborone
Botswana-harvard Laboratory
Moïsi, Daniella D.
Canada, Montreal
Sir Mortimer B. Davis Jewish General Hospital
Ntemgwa, Michel Lemonge
Canada, Montreal
Sir Mortimer B. Davis Jewish General Hospital
Frankel, Fernando A.
Canada, Montreal
Sir Mortimer B. Davis Jewish General Hospital
Essex, Max E.
Botswana, Gaborone
Botswana-harvard Laboratory
Wainberg, Mark A.
Canada, Montreal
Sir Mortimer B. Davis Jewish General Hospital
Statistics
Citations: 237
Authors: 8
Affiliations: 2
Identifiers
Doi:
10.1097/01.aids.0000232228.88511.0b
Research Areas
Cancer
Infectious Diseases