Impact of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor Drug Resistance Mutation Interactions on Phenotypic Susceptibility
| Autor: | Daniel R. Rojo, Miguel Montes-Walters, Vinod Trivedi, Neil Parkin, Elisabeth J. Shell, Monique R. Ferguson, William A. O'Brien, Jana J. von Lindern |
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| Rok vydání: | 2008 |
| Předmět: |
Immunology
Mutation Missense HIV Infections Drug resistance Biology Virus Replication Inhibitory Concentration 50 Zidovudine Abacavir Virology Drug Resistance Viral medicine Humans Didanosine Recombination Genetic Reverse Transcriptase Polymerase Chain Reaction Stavudine virus diseases Lamivudine Resistance mutation HIV Reverse Transcriptase Reverse transcriptase Infectious Diseases HIV-1 RNA Viral Reverse Transcriptase Inhibitors medicine.drug |
| Zdroj: | AIDS Research and Human Retroviruses. 24:1291-1300 |
| ISSN: | 1931-8405 0889-2229 |
| DOI: | 10.1089/aid.2007.0244 |
| Popis: | The role specific reverse transcriptase (RT) drug resistance mutations play in influencing phenotypic susceptibility to RT inhibitors in virus strains with complex resistance interaction patterns was assessed using recombinant viruses that consisted of RT-PCR-amplified pol fragments derived from plasma HIV-1 RNA from two treatment-experienced patients. Specific modifications of key RT amino acids were performed by site-directed mutagenesis. A panel of viruses with defined genotypic resistance mutations was assessed for phenotypic drug resistance. Introduction of M184V into several different clones expressing various RT resistance mutations uniformly decreased susceptibility to abacavir, lamivudine, and didanosine, and increased susceptibility to zidovudine, stavudine, and tenofovir; replication capacity was decreased. The L74V mutation had similar but slightly different effects, contributing to decreased susceptibility to abacavir, lamivudine, and didanosine and increased susceptibility to zidovudine and tenofovir, but in contrast to M184V, L74V contributed to decreased susceptibility to stavudine. In virus strains with the nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E and G190S, the L74V mutation increased replication capacity, consistent with published observations, but replication capacity was decreased in strains without NNRTI resistance mutations. K101E and G190S together tend to decrease susceptibility to all nucleoside RT inhibitors, but the K103N mutation had little effect on nucleoside RT inhibitor susceptibility. Mutational interactions can have a substantial impact on drug resistance phenotype and replication capacity, and this has been exploited in clinical practice with the development of fixed-dose combination pills. However, we are the first to report these mutational interactions using molecularly cloned recombinant strains derived from viruses that occur naturally in HIV-infected individuals. |
| Databáze: | OpenAIRE |
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