Resistance to raltegravir highlights integrase mutations at codon 148 in conferring cross-resistance to a second-generation HIV-1 integrase inhibitor

Goethals, Olivia; Ginderen, Marcia Van; Vos, Ann; Cummings, Maxwell D.; Borght, Koen Van der; Wesenbeeck, Liesbeth Van; Feyaerts, Maxim; Verheyen, Ann; Smits, Veerle; Loock, Marnix Van; Hertogs, Kurt; Schols, Dominique; Clayton, R. M.

doi:10.1016/j.antiviral.2011.05.011

Cited by 29 publications

(28 citation statements)

References 41 publications

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“…However, fold changes (FC) in susceptibility were moderate (FC, Ͻ2.5) for all of these substitutions; the substitutions at the well-characterized polymorphic positions L101 and T124 did not increase DTG or RAL FC (33, 68). Although no major resistance mutation against DTG has been identified to date, thus far the accumulation of multiple mutations is required to result in an FC of Ͼ10, confirming that second-generation INSTIs possess a higher genetic barrier for resistance than their first-generation counterparts (20,33).To further investigate this subject, we performed in vitro selections with DTG using viruses of subtypes B, C, and recombinant A/G. The most common mutation selected was R263K, and introduction of R263K into HIV-1 pNL4-3 by site-directed mutagenesis revealed low-level resistance to DTG.…”

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confidence: 99%

“…Secondgeneration INSTIs have been developed, which possess a more robust resistance profile than RAL and EVG (3,21,27,33,67). These include MK-2048 (3, 4, 20, 67) and dolutegravir (DTG) (3,20,33,45,46,61,67).Selection studies have shown that MK-2048 can select a G118R resistance mutation (3), and during similar studies with DTG, changes were observed at positions E92, L101, T124, S153, and G193 (33,57,59). However, fold changes (FC) in susceptibility were moderate (FC, Ͻ2.5) for all of these substitutions; the substitutions at the well-characterized polymorphic positions L101 and T124 did not increase DTG or RAL FC (33, 68).…”

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Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Quashie

Mésplède

Han

et al. 2012

J Virol

214

306

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Integrase (IN) strand transfer inhibitors (INSTIs) have been developed to inhibit the ability of HIV-1 integrase to irreversibly link the reverse-transcribed viral DNA to the host genome. INSTIs have proven their high efficiency in inhibiting viral replication in vitro and in patients. However, first-generation INSTIs have only a modest genetic barrier to resistance, allowing the virus to escape these powerful drugs through several resistance pathways. Second-generation INSTIs, such as dolutegravir (DTG, S/GSK1349572), have been reported to have a higher resistance barrier, and no novel drug resistance mutation has yet been described for this drug. Therefore, we performed in vitro selection experiments with DTG using viruses of subtypes B, C, and A/G and showed that the most common mutation to emerge was R263K. Further analysis by site-directed mutagenesis showed that R263K does confer low-level resistance to DTG and decreased integration in cell culture without altering reverse transcription. Biochemical cell-free assays performed with purified IN enzyme containing R263K confirmed the absence of major resistance against DTG and showed a slight decrease in 3= processing and strand transfer activities compared to the wild type. Structural modeling suggested and in vitro IN-DNA binding assays show that the R263K mutation affects IN-DNA interactions.T he high mutation rate of HIV-1 reverse transcriptase (RT) allows the virus to escape pressure through adaptive mutations that include drug resistance mutations that limit the effectiveness of antiretroviral drugs (5,31,66,69,70). The use of multiple drugs in combination can hamper this process by restraining viral replication, limiting the emergence of resistant strains. The addition of integrase inhibitors to the arsenal of drugs against HIV-1 is important since these inhibitors are active against viruses resistant to other drug classes (16,49,63).The HIV-1 integrase enzyme catalyzes two reactions. The first is 3= processing, which consists of cleavage of a dinucleotide at both 3= ends of the reverse-transcribed linear viral DNA and results in the exposure of reactive hydroxyl groups. The second step termed "strand transfer" is carried out through a nucleophilic attack by exposed 3= hydroxyl groups on host genomic DNA (26, 47). Even though 3= processing may be a suitable therapeutic target, the integrase inhibitors developed so far are integrase strand transfer inhibitors (INSTIs) that preferentially inhibit strand transfer while only modestly affecting 3= processing (18,24,26). Raltegravir (RAL) was the first INSTI to be approved for therapy in 2007 (64) and is safe and efficient in both treatment-naïve and treatment-experienced subjects (11,17,23,35,49,62,63). Elvitegravir (EVG) is another INSTI currently in advanced clinical trials (10,12,77).Although first-generation INSTIs strongly inhibit HIV-1 replication, they possess only a modest genetic barrier to resistance. Three main resistance pathways have been identified for RAL, involving initial mutations of the N1...

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confidence: 99%

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Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Quashie

Mésplède

Han

et al. 2012

J Virol

214

306

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“…HAART has an achievement on reducing disease progression, but it is also related to collateral problems like resistance of antivirals, toxicity and dosing which are preventing successful treatment of HIV [8,[10][11][12][13][14][15][16][17][18][19]. These shortfalls of HAART drugs' combinations point out the need for new drugs.…”

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confidence: 99%

“…However, instead of using single drugs, a combination of RT and PR drugs, named Highly Active Antiretroviral Therapy (HAART) is used to suppress viral replication of HIV-1 [7][8][9].…”

Section: Human Immunodeficiency Virus (Hiv) Is a Member Of Lentivirusmentioning

confidence: 99%

Docking and Molecular Dynamics Calculations of Some Previously Studied and newly Designed Ligands to Catalytic Core Domain of HIV-1 Integrase and an Investigation to Effects of Conformational Changes of Protein on Docking Results

Ercan¹

2016

Journal of the Turkish Chemical Society, Section A: Chemistry

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Nowadays, AIDS still remains as a worldwide pandemic and continues to cause many deaths which arise from HIV-1 virus. For nearly 35 years, drugs that target various steps of virus life cycle have been developed. HIV-1 integrase constitutes one of these steps which is essential for virus life cycle. Computer-aided drug design is being used in many drug development and drug improvement studies as also used in development of the first HIV-1 integrase inhibitor Raltegravir. In this study, 3 ligands which are already used as HIV-1 integrase inhibitors and 4 newly designed ligands were docked to catalytic core domain of HIV-1 integrase. Each ligand docked to three different conformations of protein. Prepared complexes (21 items) were carried out by 50 ns MD simulations and results were analyzed. Finally, the binding free energies of ligands were calculated. It was determined that designed ligands L01 and L03 gave favorable results. The questions about the ligands which have low docking scores in a conformation of protein could give better scores in another conformation of protein and if the MD simulations carry the different oriented and different localized ligands in same position at the end of simulation were answered.

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HIV-1 Integrase Drug Discovery Comes of Age

Demeulemeester

Maeyer

Debyser

2013

Topics in Medicinal Chemistry

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Resistance to raltegravir highlights integrase mutations at codon 148 in conferring cross-resistance to a second-generation HIV-1 integrase inhibitor

Cited by 29 publications

References 41 publications

Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Docking and Molecular Dynamics Calculations of Some Previously Studied and newly Designed Ligands to Catalytic Core Domain of HIV-1 Integrase and an Investigation to Effects of Conformational Changes of Protein on Docking Results

HIV-1 Integrase Drug Discovery Comes of Age

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