Dataset Information

Emergence of the G118R Pan-Integrase Resistance Mutation as a Result of Low Compliance to a Dolutegravir-Based cART.

ABSTRACT: HIV-1 resistance towards integrase inhibitors is a potential threat of the success of HIV-1 combination treatment. G118R is a rare drug resistance mutation conferring pan-integrase resistance. Here, we describe the occurrence of G118R in a HIV-1 subtype-B-positive individual with major compliance problems, detected while the patient was on dolutegravir-based cART. We speculate the pre-selection of M184I/V aided the occurrence of G118R in this case, and discuss the robustness of dolutegravir-based therapies.

SUBMITTER: Mens H

PROVIDER: S-EPMC9326666 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Emergence of the G118R Pan-Integrase Resistance Mutation as a Result of Low Compliance to a Dolutegravir-Based cART.

Mens Helene H Fjordside Lasse L Fonager Jannik J Gerstoft Jan J

Infectious disease reports 20220622 4

HIV-1 resistance towards integrase inhibitors is a potential threat of the success of HIV-1 combination treatment. G118R is a rare drug resistance mutation conferring pan-integrase resistance. Here, we describe the occurrence of G118R in a HIV-1 subtype-B-positive individual with major compliance problems, detected while the patient was on dolutegravir-based cART. We speculate the pre-selection of M184I/V aided the occurrence of G118R in this case, and discuss the robustness of dolutegravir-base ...[more]

PMID: 35893472

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Project description:P1093 is a multicenter, open-label, phase I/II study of pharmacokinetics, safety, and tolerability of dolutegravir plus an optimized background regimen in pediatric participants aged 4 weeks to <18 years with HIV-1. Most participants were highly treatment experienced. We report the mechanisms of emergent integrase strand transfer inhibitor (INSTI) resistance among adolescents and children receiving dolutegravir. Plasma was collected at screening and near protocol-defined virologic failure (PDVF) for population-level and, for some samples, clonal-level integrase genotyping, phenotyping, and replication capacity. HIV-1 RNA was assessed in all available plasma samples. Phylogenetic analysis of clonal integrase sequences and homology modeling of HIV-1 intasome complexes containing resistance-associated substitutions were performed. Treatment-emergent INSTI resistance was detected in 8 participants who met PDVF criteria. The rare INSTI resistance-associated substitution G118R or R263K developed in 6 participants. The on-study secondary integrase substitution E157Q or L74I was observed in 2 participants. G118R reduced dolutegravir susceptibility and integrase replication capacity more than R263K and demonstrated greater reduction in susceptibility and integrase replication capacity when present with specific secondary integrase substitutions, including L74M, T66I, and E138E/K. Continuing evolution after R263K acquisition led to reduced dolutegravir susceptibility and integrase replication capacity. Structural examination revealed potential mechanisms for G118R- and R263K-mediated INSTI resistance. G118R and R263K INSTI resistance substitutions, which are distinct to second-generation INSTIs, were detected in adolescents and children with prior virologic failure who received dolutegravir. This study provides additional molecular and structural characterization of integrase to aid in the understanding of INSTI resistance mechanisms in antiretroviral-experienced populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01302847.).

Project description:UnlabelledDolutegravir (DTG) is the latest antiretroviral (ARV) approved for the treatment of human immunodeficiency virus (HIV) infection. The G118R substitution, previously identified with MK-2048 and raltegravir, may represent the initial substitution in a dolutegravir resistance pathway. We have found that subtype C integrase proteins have a low enzymatic cost associated with the G118R substitution, mostly at the strand transfer step of integration, compared to either subtype B or recombinant CRF02_AG proteins. Subtype B and circulating recombinant form AG (CRF02_AG) clonal viruses encoding G118R-bearing integrases were severely restricted in their viral replication capacity, and G118R/E138K-bearing viruses had various levels of resistance to dolutegravir, raltegravir, and elvitegravir. In cell-free experiments, the impacts of the H51Y and E138K substitutions on resistance and enzyme efficiency, when present with G118R, were highly dependent on viral subtype. Sequence alignment and homology modeling showed that the subtype-specific effects of these mutations were likely due to differential amino acid residue networks in the different integrase proteins, caused by polymorphic residues, which significantly affect native protein activity, structure, or function and are important for drug-mediated inhibition of enzyme activity. This preemptive study will aid in the interpretation of resistance patterns in dolutegravir-treated patients.ImportanceRecognized drug resistance mutations have never been reported for naive patients treated with dolutegravir. Additionally, in integrase inhibitor-experienced patients, only R263K and other previously known integrase resistance substitutions have been reported. Here we suggest that alternate resistance pathways may develop in non-B HIV-1 subtypes and explain how "minor" polymorphisms and substitutions in HIV integrase that are associated with these subtypes can influence resistance against dolutegravir. This work also highlights the importance of phenotyping versus genotyping when a strong inhibitor such as dolutegravir is being used. By characterizing the G118R substitution, this work also preemptively defines parameters for a potentially important pathway in some non-B HIV subtype viruses treated with dolutegravir and will aid in the inhibition of such a virus, if detected. The general inability of strand transfer-related substitutions to diminish 3' processing indicates the importance of the 3' processing step and highlights a therapeutic angle that needs to be better exploited.

Dataset Information

Emergence of the G118R Pan-Integrase Resistance Mutation as a Result of Low Compliance to a Dolutegravir-Based cART.

Publications

Emergence of the G118R Pan-Integrase Resistance Mutation as a Result of Low Compliance to a Dolutegravir-Based cART.

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