ArticleJournal of virology2008
Ninety-nine is not enough: molecular characterization of inhibitor-resistant human immunodeficiency virus type 1 protease mutants with insertions in the flap region.
Article in Journal of virology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 48 citations in OpenAlex.
- Subtype-Specific HIV-1 Protease and the Role of Hinge and Flap Dynamics in Drug Resistance: A Subtype C Narrative.Viruses · 2025Review
- Understanding Drug Resistance of Wild-Type and L38HL Insertion Mutant of HIV-1 C Protease to Saquinavir.Genes · 2023Article
- Management of Antiretroviral Therapy with Boosted Protease Inhibitors-Darunavir/Ritonavir or Darunavir/Cobicistat.Biomedicines · 2021Review
- Bioinformatic data processing pipelines in support of next-generation sequencing-based HIV drug resistance testing: the Winnipeg Consensus.Journal of the International AIDS Society · 2018Article
- Structural and biochemical characterization of a novel aminopeptidase from human intestine.The Journal of biological chemistry · 2015Article
- Highly resistant HIV-1 proteases and strategies for their inhibition.Future medicinal chemistry · 2015Review
- Article
- GS-8374, a prototype phosphonate-containing inhibitor of HIV-1 protease, effectively inhibits protease mutants with amino acid insertions.Journal of virology · 2014Article
- Novel codon insert in HIV type 1 clade B reverse transcriptase associated with low-level viremia during antiretroviral therapy.AIDS research and human retroviruses · 2014Article
- Mutations in HIV-1 gag and pol compensate for the loss of viral fitness caused by a highly mutated protease.Antimicrobial agents and chemotherapy · 2012Article
- HIV-1 protease with 20 mutations exhibits extreme resistance to clinical inhibitors through coordinated structural rearrangements.Biochemistry · 2012Article
- Protease-Mediated Maturation of HIV: Inhibitors of Protease and the Maturation Process.Molecular biology international · 2012Article
- HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat.Retrovirology · 2011Article
- Machine learning on normalized protein sequences.BMC research notes · 2011Article
- Computational analysis of HIV-1 protease protein binding pockets.Journal of chemical information and modeling · 2010Article
- Computational mutation scanning and drug resistance mechanisms of HIV-1 protease inhibitors.The journal of physical chemistry. B · 2010Article
- Current and Novel Inhibitors of HIV Protease.Viruses · 2009Article
- Article
- Molecular characterization of clinical isolates of human immunodeficiency virus resistant to the protease inhibitor darunavir.Journal of virology · 2009Article
- A novel codon insert in protease of clade B HIV type 1.AIDS research and human retroviruses · 2009Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
While the selection of amino acid insertions in human immunodeficiency virus (HIV) reverse transcriptase (RT) is a known mechanism of resistance against RT inhibitors, very few reports on the selection of insertions in the protease (PR) coding region have been published. It is still unclear whether these insertions impact protease inhibitor (PI) resistance and/or viral replication capacity. We show that the prevalence of insertions, especially between amino acids 30 to 41 of HIV type 1 (HIV-1) PR, has increased in recent years. We identified amino acid insertions at positions 33 and 35 of the PR of HIV-1-infected patients who had undergone prolonged treatment with PIs, and we characterized the contribution of these insertions to viral resistance. We prepared the corresponding mutated, recombinant PR variants with or without insertions at positions 33 and 35 and characterized them in terms of enzyme kinetics and crystal structures. We also engineered the corresponding recombinant viruses and analyzed the PR susceptibility and replication capacity by recombinant virus assay. Both in vitro methods confirmed that the amino acid insertions at positions 33 and 35 contribute to the viral resistance to most of the tested PIs. The structural analysis revealed local structural rearrangements in the flap region and in the substrate binding pockets. The enlargement of the PR substrate binding site together with impaired flap dynamics could account for the weaker inhibitor binding by the insertion mutants. Amino acid insertions in the vicinity of the binding cleft therefore represent a novel mechanism of HIV resistance development.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.