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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kulkarni, Rima Babaoglu, Kerim Lansdon, Eric B. Rimsky, Laurence Van Eygen, Veerle Picchio, Gaston Svarovskaia, Evguenia Miller, Michael D. White, Kirsten L. |
| Description | Country affiliation: United States Author Affiliation: Kulkarni R ( Clinical Virology, Gilead Sciences, Inc, Foster City, CA, USA.) |
| Abstract | BACKGROUND: The registrational phase III clinical trials of the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) rilpivirine (RPV) in combination with two nucleoside/nucleotide RT inhibitors (NRTIs) found a unique genotypic resistance pattern involving the NNRTI mutation E138K with the NRTI mutation M184I. Eighty percent of subjects used emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF); a single tablet regimen of FTC/RPV/TDF is in development. METHODS: HIV-1 with E138K and/or M184V or I mutations were constructed and phenotyped in MT-2 cells and the PhenoSense and Antivirogram assays. Viral fitness was determined using growth competitions. Molecular models of the mutants were constructed from the RT-RPV crystal structure. RESULTS: The E138K mutant showed low-level reduced susceptibility to RPV (2.4-fold), but full susceptibility to FTC and tenofovir (TFV). Viruses with M184V or M184I showed high-level resistance to FTC and full susceptibility to RPV and TFV. Addition of M184I, but not M184V, to E138K, further decreased susceptibility to RPV and maintained FTC resistance. The E138K and M184V or I single and double mutants showed decreased replication fitness compared with wild type. M184V outcompeted M184I when compared directly and in the background of E138K. E138K + M184I was less fit than either E138K or M184I alone. Removing a salt bridge between E138/K101 is implicated in resistance to RPV. CONCLUSIONS: The higher frequency of E138K and M184I among RPV + FTC/TDF virologic failures is due to reduced susceptibility of the single mutants to RPV and FTC and the enhanced resistance to RPV for the double mutant at the cost of decreased viral fitness. |
| File Format | HTM / HTML |
| ISSN | 15254135 |
| Issue Number | 1 |
| Volume Number | 59 |
| e-ISSN | 10779450 |
| Journal | JAIDS Journal of Acquired Immune Deficiency Syndromes |
| Language | English |
| Publisher | Lippincott Williams & Wilkins |
| Publisher Date | 2012-01-01 |
| Publisher Place | United States |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Discipline AIDS Anti-hiv Agents Therapeutic Use Drug Resistance, Viral Genetics Hiv Reverse Transcriptase Hiv-1 Drug Effects Nitriles Pyrimidines Pharmacology Gene Expression Regulation, Enzymologic Gene Expression Regulation, Viral Physiology Metabolism Humans Models, Molecular Mutation Protein Conformation Rna, Viral Rilpivirine Virus Replication Journal Article |
| Content Type | Text |
| Resource Type | Article |
| Subject | Infectious Diseases Pharmacology (medical) |
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