Connection Subdomain Mutations in HIV-1 Subtype-C Treatment-Experienced Patients Enhance NRTI and NNRTI Drug Resistance
| Autor: | Marcelo A. Soares, Krista A. Delviks-Frankenberry, Jussara Maria Silveira, Vinay K. Pathak, André F. Santos, Frank Maldarelli, Mary F. Kearney, Renan B. Lengruber |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
NNRTI
Anti-HIV Agents Molecular Sequence Data Etravirine HIV Infections Drug resistance Biology medicine.disease_cause Article Cell Line chemistry.chemical_compound Zidovudine Virology Drug Resistance Viral Nitriles medicine Humans Amino Acid Sequence RNase H Mutation virus diseases Subtype C Reverse transcriptase HIV Reverse Transcriptase Protein Structure Tertiary Pyridazines Pyrimidines chemistry NRTI biology.protein HIV-1 Connection domain Reverse Transcriptase Inhibitors Thymidine Nucleoside Brazil medicine.drug |
| Popis: | Mutations in the connection subdomain (CN) and RNase H domain (RH) of HIV-1 reverse transcriptase (RT) from subtype B-infected patients enhance nucleoside and nonnucleoside RT inhibitor (NRTI and NNRTI) resistance by affecting the balance between polymerization and RNase H activity. To determine whether CN mutations in subtype C influence drug sensitivity, single genome sequencing was performed on Brazilian subtype C-infected patients failing RTI therapy. CN mutations identified were similar to subtype B, including A376S, A400T, Q334D, G335D, N348I, and A371V, and increased AZT resistance in the presence of thymidine analog mutations. CN mutations also enhanced NNRTI resistance in the presence of classical NNRTI mutations: etravirine resistance was enhanced 6- to 11-fold in the presence of L100I/K103N/Y181C. These results indicate that selection of CN mutations in treatment-experienced patients also occurs in subtype-C-infected patients and are likely to provide valuable information in predicting clinical RTI resistance. |
| Databáze: | OpenAIRE |
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