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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

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. CONCLUSION: Tenofovir -based regimens will need to be carefully monitored in subtype C infections for the possible selection of K65R.[1]

References

  1. HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture. Brenner, B.G., Oliveira, M., Doualla-Bell, F., Moisi, D.D., Ntemgwa, M., Frankel, F., Essex, M., Wainberg, M.A. AIDS (2006) [Pubmed]
 
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