Clonal Resistance Analyses of HIV-1 after Failure of Therapy with Didanosine, Lamivudine, and Tenofovir
| Autor: | Dianna Koontz, Douglas Barnas, Christian J. Bixby, Holly Bazmi, John W. Mellors, Joseph G. Jemsek |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Tenofovir
Genotype Anti-HIV Agents Human immunodeficiency virus (HIV) Organophosphonates HIV Infections Genome Viral medicine.disease_cause Article Zidovudine immune system diseases Drug Resistance Viral medicine Humans Pharmacology (medical) Treatment Failure Initial therapy Didanosine Pharmacology Recombination Genetic business.industry Adenine virus diseases Lamivudine Sequence Analysis DNA biochemical phenomena metabolism and nutrition Virology Reverse transcriptase HIV Reverse Transcriptase Infectious Diseases Phenotype Mutation HIV-1 Reverse Transcriptase Inhibitors Drug Therapy Combination business Nucleoside medicine.drug |
| Popis: | Background The rapid failure of initial therapy with combinations of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) that exclude zidovudine has not been fully explained by standard virus population analyses of HIV type-1 (HIV-1) drug resistance. We therefore investigated HIV-1 genotype and phenotype at the single genome level in samples from patients on a failing regimen of tenofovir (TNV), didanosine (ddI) and lamivudine (3TC). Methods Single genome sequencing was performed on 9 failure samples containing both K65R and M184V mutations by standard genotype, either as wild-type/mutant mixtures (6/9) or as mutant only (3/9). Recombinant clones with different combinations of observed mutations were generated and tested for NRTI susceptibility. Results Of the 204 single genome sequences analysed, 50% were K65R/M184V double mutants, 38% were M184V single mutants, 10% were M184I single mutants and only 1% (2 sequences) were K65R single mutants. Phenotypic testing of recombinant clones showed a significant increase in resistance for double mutants: mean fold resistance to abacavir, ddI and TNV was 6.5, 4.3 and 1.6 for K65R/M184V double mutants versus 2.5, 1.9 and 0.6 for M184V single mutants, respectively ( PConclusions Mutants with K65R and M184V linked on the same genome were the most common HIV-1 variants in samples analysed from patients failing TNV, ddI and 3TC with both mutations detected by standard genotype. The double mutant exhibited reduced susceptibility to all three NRTIs in the regimen. This resistant phenotype, resulting from just two linked point mutations, likely contributes to rapid failure of NRTI combinations that exclude zidovudine. |
| Databáze: | OpenAIRE |
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