Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility.
| Title: | Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility. |
|---|---|
| Authors: | Trivedi V; Department of Internal Medicine, Division of Infectious Diseases, The University of Texas Medical Branch, Galveston, Texas 77555-0435, USA.; Von Lindern J; Montes-Walters M; Rojo DR; Shell EJ; Parkin N; O'Brien WA; Ferguson MR |
| Source: | AIDS research and human retroviruses [AIDS Res Hum Retroviruses] 2008 Oct; Vol. 24 (10), pp. 1291-300. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Mary Ann Liebert Country of Publication: United States NLM ID: 8709376 Publication Model: Print Cited Medium: Internet ISSN: 1931-8405 (Electronic) Linking ISSN: 08892229 NLM ISO Abbreviation: AIDS Res Hum Retroviruses Subsets: MEDLINE |
| Imprint Name(s): | Publication: Larchmont, NY : Mary Ann Liebert; Original Publication: [New York] : Mary Ann Liebert, [c1987- |
| MeSH Terms: | Drug Resistance, Viral* ; Mutation, Missense*; HIV Reverse Transcriptase/*genetics ; HIV-1/*drug effects ; HIV-1/*genetics ; Reverse Transcriptase Inhibitors/*pharmacology; HIV Infections/virology ; RNA, Viral/blood ; RNA, Viral/genetics ; Virus Replication/drug effects ; Humans ; Inhibitory Concentration 50 ; Recombination, Genetic ; Reverse Transcriptase Polymerase Chain Reaction |
| Abstract: | 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. |
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| Grant Information: | R01 HL088999 United States HL NHLBI NIH HHS |
| Substance Nomenclature: | 0 (RNA, Viral); 0 (Reverse Transcriptase Inhibitors); EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1); EC 2.7.7.49 (HIV Reverse Transcriptase) |
| Entry Date(s): | Date Created: 20081011 Date Completed: 20081118 Latest Revision: 20250529 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC2721781 |
| DOI: | 10.1089/aid.2007.0244 |
| PMID: | 18844463 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't