ArticleThe Journal of antimicrobial chemotherapy2016
Polymorphic substitution E157Q in HIV-1 integrase increases R263K-mediated dolutegravir resistance and decreases DNA binding activity.
Article in The Journal of antimicrobial chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 45 citations in OpenAlex.
- Article
- Resistance Trends of Antiretroviral Agents in People with Human Immunodeficiency Virus in Korea, 2012 - 2020.Infection & chemotherapy · 2023Article
- 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
- Prevalence of HIV-1 Natural Polymorphisms and Integrase-Resistance-Associated Mutations in African Children.Viruses · 2023Article
- Affordable drug resistance genotyping of HIV-1 reverse transcriptase, protease and integrase genes, for resource limited settings.AIDS research and therapy · 2023Article
- Pre-Treatment Integrase Inhibitor Resistance and Natural Polymorphisms among HIV-1 Subtype C Infected Patients in Ethiopia.Viruses · 2022Article
- Statewide Longitudinal Trends in Transmitted HIV-1 Drug Resistance in Rhode Island, USA.Open forum infectious diseases · 2022Article
- Genetic Diversity and Low Therapeutic Impact of Variant-Specific Markers in HIV-1 Pol Proteins.Frontiers in microbiology · 2022Article
- Transmitted HIV drug resistance and subtype patterns among blood donors in Poland.Scientific reports · 2021Article
- Interaction analysis of statistically enriched mutations identified in Cameroon recombinant subtype CRF02_AG that can influence the development of Dolutegravir drug resistance mutations.BMC infectious diseases · 2021Article
- Low Frequency of Integrase Inhibitor Resistance Mutations Among Therapy-Naïve HIV Patients in Southeast China.Drug design, development and therapy · 2021Article
- HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants.Antimicrobial agents and chemotherapy · 2020Article
- HIV-1 acquired drug resistance to integrase inhibitors in a cohort of antiretroviral therapy multi-experienced Mexican patients failing to raltegravir: a cross-sectional study.AIDS research and therapy · 2020Article
- Virological Failure in HIV to Triple Therapy With Dolutegravir-Based Firstline Treatment: Rare but Possible.Open forum infectious diseases · 2019Article
- Observational
- Ultra-long-acting removable drug delivery system for HIV treatment and prevention.Nature communications · 2018Article
- Integrase Strand Transfer Inhibitor Resistance Mutations in Antiretroviral Treatment-naïve Patients in Korea: a Prospective, Observational Study.Journal of Korean medical science · 2018Observational
- Absence of HIV-1 Drug Resistance Mutations Supports the Use of Dolutegravir in Uganda.AIDS research and human retroviruses · 2018Article
- Prevalence of Primary Drug Resistance Against HIV-1 Integrase Inhibitors in Canada.Journal of acquired immune deficiency syndromes (1999) · 2018Article
- Analyses of HIV-1 integrase sequences prior to South African national HIV-treatment program and available of integrase inhibitors in Cape Town, South Africa.Scientific reports · 2018Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
objectivesThe E157Q substitution in HIV-1 integrase (IN) is a relatively common natural polymorphism associated with HIV resistance to IN strand transfer inhibitors (INSTIs). Although R263K is the most common resistance substitution for the INSTI dolutegravir, an INSTI treatment-experienced individual recently failed dolutegravir-based therapy, with E157Q being the only resistance-associated change reported. Given that different resistance pathways can sometimes synergize to confer high levels of resistance to antiretroviral drugs, we studied the effects of E157Q in association with R263K. Because Glu157 is thought to lie within the binding site of HIV IN DNA binding inhibitors such as FZ41, we also evaluated DNA binding activity and resistance to IN inhibitors in the presence of E157Q.
methodsPurified recombinant IN proteins were assessed in cell-free assays for their strand transfer and DNA binding activities. NL4.3 viral stocks harbouring IN mutations were generated and characterized in the presence and absence of IN inhibitors in tissue culture.
resultsE157Q alone had little if any effect on the biochemical activity of IN, and partially restored the activity of R263K-containing IN. The E157Q/R263K double viral mutant displayed infectiousness in culture equivalent to WT, while increasing resistance to dolutegravir by 10-fold compared with lower-level resistance associated with R263K alone. None of the mutations tested showed significant resistance to either raltegravir or FZ41.
conclusionsThis study shows that E157Q may act as a compensatory mutation for R263K. Since E157Q is a natural polymorphism present in 1%-10% of HIV-positive individuals, it may be of particular importance for patients receiving INSTI therapy.
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