ArticleAntimicrobial agents and chemotherapy2013
Biochemical analysis of the role of G118R-linked dolutegravir drug resistance substitutions in HIV-1 integrase.
Article in Antimicrobial agents and chemotherapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 45 papers, 1 of them a synthesis that pooled it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it.
- A systematic review of the genetic mechanisms of dolutegravir resistance.The Journal of antimicrobial chemotherapy · 2019Pooled it
- Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study.Antimicrobial agents and chemotherapy · 2022Trial
- Integrase Inhibitor Resistance Mechanisms and Structural Characteristics in Antiretroviral Therapy-Experienced, Integrase Inhibitor-Naive Adults with HIV-1 Infection Treated with Dolutegravir plus Two Nucleoside Reverse Transcriptase Inhibitors in the DAWNING Study.Antimicrobial agents and chemotherapy · 2022Trial
- Cooperation between HIV-1 integrase natural polymorphism K156N and 3'PPT mutations in dolutegravir monotherapy failure.The Journal of antimicrobial chemotherapy · 2026Article
- Computational and Population-Based HLA Permissiveness to HIV Drug Resistance-Associated Mutations.Pathogens (Basel, Switzerland) · 2025Article
- Article
- The G118R plus R263K Combination of Integrase Mutations Associated with Dolutegravir-Based Treatment Failure Reduces HIV-1 Replicative Capacity and Integration.Antimicrobial agents and chemotherapy · 2023Article
- Emergence of the G118R Pan-Integrase Resistance Mutation as a Result of Low Compliance to a Dolutegravir-Based cART.Infectious disease reports · 2022Article
- HIV-1 Integrase Inhibitors with Modifications That Affect Their Potencies against Drug Resistant Integrase Mutants.ACS infectious diseases · 2021Article
- Retroviral integrase: Structure, mechanism, and inhibition.The Enzymes · 2021Article
- 2019 update of the drug resistance mutations in HIV-1.Topics in antiviral medicine · 2019Article
- HIV-1 Integrase Inhibitors That Are Broadly Effective against Drug-Resistant Mutants.Antimicrobial agents and chemotherapy · 2018Article
- Efficacies of Cabotegravir and Bictegravir against drug-resistant HIV-1 integrase mutants.Retrovirology · 2018Article
- Human Immunodeficiency Virus Type 1 Drug Resistance Mutations Update.The Journal of infectious diseases · 2017Article
- Current Status of Point-of-Care Testing for Human Immunodeficiency Virus Drug Resistance.The Journal of infectious diseases · 2017Review
- Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1.Antimicrobial agents and chemotherapy · 2017Article
- HIV-1 strains belonging to large phylogenetic clusters show accelerated escape from integrase inhibitors in cell culture compared with viral isolates from singleton/small clusters.The Journal of antimicrobial chemotherapy · 2017Article
- Tribute to Mark Wainberg.Retrovirology · 2017Article
- HIV drug resistance against strand transfer integrase inhibitors.Retrovirology · 2017Review
- Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation.PloS one · 2017Article
Corrections and comments
- Erratum issued
Authors and funding
9 authors.
Funding
Abstract
Drug resistance mutations (DRMs) have been reported for all currently approved anti-HIV drugs, including the latest integrase strand transfer inhibitors (INSTIs). We previously used the new INSTI dolutegravir (DTG) to select a G118R integrase resistance substitution in tissue culture and also showed that secondary substitutions emerged at positions H51Y and E138K. Now, we have characterized the impact of the G118R substitution, alone or in combination with either H51Y or E138K, on 3' processing and integrase strand transfer activity. The results show that G118R primarily impacted the strand transfer step of integration by diminishing the ability of integrase-long terminal repeat (LTR) complexes to bind target DNA. The addition of H51Y and E138K to G118R partially restored strand transfer activity by modulating the formation of integrase-LTR complexes through increasing LTR DNA affinity and total DNA binding, respectively. This unique mechanism, in which one function of HIV integrase partially compensates for the defect in another function, has not been previously reported. The G118R substitution resulted in low-level resistance to DTG, raltegravir (RAL), and elvitegravir (EVG). The addition of either of H51Y or E138K to G118R did not enhance resistance to DTG, RAL, or EVG. Homology modeling provided insight into the mechanism of resistance conferred by G118R as well as the effects of H51Y or E138K on enzyme activity. The G118R substitution therefore represents a potential avenue for resistance to DTG, similar to that previously described for the R263K substitution. For both pathways, secondary substitutions can lead to either diminished integrase activity and/or increased INSTI susceptibility.
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