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Pathway involving the N155H mutation in HIV-1 integrase leads to dolutegravir resistance

Published on May 1, 2018in Journal of Antimicrobial Chemotherapy5.113
· DOI :10.1093/jac/dkx529
Isabelle Malet25
Estimated H-index: 25
(University of Paris),
Francesca Alessandra Ambrosio3
Estimated H-index: 3
+ 13 AuthorsOlivier Delelis24
Estimated H-index: 24
(Université Paris-Saclay)
Abstract
Background: Dolutegravir, an integrase strand-transfer inhibitor (STI), shows a high genetic barrier to resistance. Dolutegravir is reported to be effective against viruses resistant to raltegravir and elvitegravir. In this study, we report the case of a patient treated with dolutegravir monotherapy. Failure of dolutegravir treatment was observed concomitant with the appearance of N155H-K211R-E212T mutations in the integrase (IN) gene in addition to the polymorphic K156N mutation that was present at baseline in this patient. Methods: The impact of N155H-K156N-K211R-E212T mutations was studied in cell-free, culture-based assays and by molecular modelling. Results: Cell-free and culture-based assays confirm that selected mutations in the patient, in the context of the polymorphic mutation K156N present at the baseline, lead to high resistance to dolutegravir requiring that the analysis be done at timepoints longer than usual to properly reveal the results. Interestingly, the association of only N155H and K156N is sufficient for significant resistance to dolutegravir. Modelling studies showed that dolutegravir is less stable in IN/DNA complexes with respect to the WT sequence. Conclusions: Our results indicate that the stability of STI IN/DNA complexes is an important parameter that must be taken into account when evaluating dolutegravir resistance. This study confirms that a pathway including N155H can be selected in patients treated with dolutegravir with the help of the polymorphic K156N that acts as a secondary mutation that enhances the resistance to dolutegravir.
  • References (29)
  • Citations (6)
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References29
Newest
#1Isabelle Malet (UPMC: Pierre-and-Marie-Curie University)H-Index: 25
#2Eloïse Thierry (CNRS: Centre national de la recherche scientifique)H-Index: 6
Last. Olivier Delelis (CNRS: Centre national de la recherche scientifique)H-Index: 24
view all 10 authors...
10 CitationsSource
#1Sylvain Thierry (CNRS: Centre national de la recherche scientifique)H-Index: 10
#2Soundasse Munir (CNRS: Centre national de la recherche scientifique)H-Index: 4
Last. Olivier Delelis (CNRS: Centre national de la recherche scientifique)H-Index: 24
view all 14 authors...
Background Genomic integration, an obligate step in the HIV-1 replication cycle, is blocked by the integrase inhibitor raltegravir. A consequence is an excess of unintegrated viral DNA genomes, which undergo intramolecular ligation and accumulate as 2-LTR circles. These circularized genomes are also reliably observed in vivo in the absence of antiviral therapy and they persist in non-dividing cells. However, they have long been considered as dead-end products that are not precursors to integrati...
29 CitationsSource
#1Soundasse Munir (CNRS: Centre national de la recherche scientifique)H-Index: 4
#2Eloïse Thierry (CNRS: Centre national de la recherche scientifique)H-Index: 6
Last. Olivier Delelis (CNRS: Centre national de la recherche scientifique)H-Index: 24
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OBJECTIVES: Strand transfer inhibitors (raltegravir, elvitegravir and dolutegravir) are now commonly used to inhibit HIV-1 integration. To date, three main pathways conferring raltegravir/elvitegravir resistance, involving residues Y143, Q148 and N155, have been described. However, no pathway has been clearly described for dolutegravir resistance. The aim of this study was to characterize the susceptibility of two mutations, F121Y and G118R, originally described in patients failing raltegravir-c...
20 CitationsSource
#1Antonella CastagnaH-Index: 40
#2Franco MaggioloH-Index: 30
Last. Jane M. Yeo (GSK: GlaxoSmithKline)H-Index: 2
view all 18 authors...
Background. The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose. Methods. VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INIresistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimiz...
162 CitationsSource
#1Isabelle Malet (French Institute of Health and Medical Research)H-Index: 25
#2Laura Gimferrer Arriaga (French Institute of Health and Medical Research)H-Index: 1
Last. Anne-Geneviève Marcelin (French Institute of Health and Medical Research)H-Index: 21
view all 13 authors...
OBJECTIVES: The possibility of replacing raltegravir or elvitegravir with dolutegravir in heavily treatment-experienced patients failing on raltegravir/elvitegravir has been evaluated in VIKING trials. All studied patients failed by the most common pathways, Y143, Q148 and N155, and dolutegravir demonstrated efficacy except for Q148 viruses. The aim of this study was to explore, in the same way, the behaviour of dolutegravir in comparison with raltegravir and elvitegravir against the atypical re...
45 CitationsSource
#1Bisher AkilH-Index: 1
#2Gary BlickH-Index: 1
Last. Mounir Ait-KhaledH-Index: 15
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Abstract The Phase III VIKING-3 study demonstrated that dolutegravir (DTG) 50 mg twice daily was efficacious in antiretroviral therapy (ART)-experienced subjects harbouring raltegravir- and/or elvitegravir-resistant HIV-1. VIKING-4 (ING116529) included a placebo-controlled 7-day monotherapy phase to demonstrate that short-term antiviral activity was attributable to DTG. VIKING-4 is a Phase III randomized, double-blind study in therapy-experienced adults with integrase inhibitor (INI)-resistant v...
35 CitationsSource
#1Filippo Canducci (UniSR: Vita-Salute San Raffaele University)H-Index: 26
#2Elisa Rita CeresolaH-Index: 10
Last. Massimo Clementi (UniSR: Vita-Salute San Raffaele University)H-Index: 42
view all 9 authors...
Objectives: The cross-resistance profiles of elvitegravir and dolutegravir on raltegravir-resistant variants is still controversial or not available in macrophages and lack extensive evaluations on wide panels of clonal variants. Thus, a complete evaluation in parallel with all currently available integrase inhibitors (INIs) was performed. Methods: The integrase coding region was RT –PCR-amplified from patient-derived plasma samples and cloned into an HIV-1 molecular clone lacking the integrase ...
28 CitationsSource
#1Soundasse Munir (École normale supérieure de Cachan)H-Index: 4
#2Sylvain Thierry (École normale supérieure de Cachan)H-Index: 10
Last. Olivier Delelis (École normale supérieure de Cachan)H-Index: 24
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Background HIV-1 DNA is found both integrated in the host chromosome and unintegrated in various forms: linear (DNAL) or circular (1-LTRc, 2-LTRc or products of auto-integration). Here, based on pre-established strategies, we extended and characterized in terms of sensitivity two methodologies for quantifying 1-LTRc and DNAL, respectively, the latter being able to discriminate between unprocessed or 3′-processed DNA.
39 CitationsSource
#1Joseph J. Eron (UNC: University of North Carolina at Chapel Hill)H-Index: 85
#2Bonaventura ClotetH-Index: 78
Last. Trevor HawkinsH-Index: 3
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Integrase inhibitors (INIs) represent a class of drugs for the treatment of human immunodeficiency virus (HIV)–infected individuals, blocking HIV genome integration into the host cell DNA [1]. They have been shown to be highly effective for the treatment of antiretroviral-naive and antiretroviral-experienced subjects, as demonstrated first with raltegravir (RAL) and more recently with elvitegravir (EVG) [2–6]. However, these first-generation INIs share common resistance pathways. In clinical stu...
171 CitationsSource
#1Carolina Garrido (ISCIII: Carlos III Health Institute)H-Index: 23
#2Jorge VillacianH-Index: 5
Last. Carmen de Mendoza (ISCIII: Carlos III Health Institute)H-Index: 35
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The failure of raltegravir (RAL) is generally associated with the selection of mutations at integrase position Y143, Q148, or N155. However, a relatively high proportion of failures occurs in the absence of these changes. Here, we report the phenotypic susceptibilities to RAL and elvitegravir (EVG) for a large group of HIV-infected patients failing on RAL-containing regimens. Plasma from HIV-infected individuals failing on RAL-containing regimens underwent genotypic and phenotypic resistance tes...
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Cited By6
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#1Alan Engelman (Harvard University)H-Index: 65
#2Peter Cherepanov (Imperial College London)H-Index: 37
Integrase strand transfer inhibitors (INSTIs) are important components of drug formulations that are used to treat people living with HIV, and second-generation INSTIs dolutegravir and bictegravir impart high barriers to the development of drug resistance. Reported 10 years ago, X-ray crystal structures of prototype foamy virus (PFV) intasome complexes explained how INSTIs bind integrase to inhibit strand transfer activity and provided initial glimpses into mechanisms of drug resistance. However...
Source
#1Soo-Yon Rhee (Stanford University)H-Index: 32
#2Philip M. Grant (Stanford University)H-Index: 14
Last. Robert W. Shafer (Stanford University)H-Index: 71
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BACKGROUND: Characterizing the mutations selected by the integrase strand transfer inhibitor (INSTI) dolutegravir and their effects on susceptibility is essential for identifying viruses less likely to respond to dolutegravir therapy and for monitoring persons with virological failure (VF) on dolutegravir therapy. METHODS: We systematically reviewed dolutegravir resistance studies to identify mutations emerging under dolutegravir selection pressure, the effect of INSTI resistance mutations on in...
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HIV-1 inserts its genetic code into human genomes, turning healthy cells into virus factories. To do this, the virus uses an enzyme called integrase. Front-line treatments against HIV-1 called “integrase strand-transfer inhibitors” stop this enzyme from working. These inhibitors have helped to revolutionize the treatment of HIV/AIDS by protecting the cells from new infections. But, the emergence of drug resistance remains a serious problem. As the virus evolves, it changes the shape of its integ...
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#1Nadia Ahmed (Central and North West London NHS Foundation Trust)H-Index: 1
#2S Flavell (Central and North West London NHS Foundation Trust)H-Index: 1
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: Dolutegravir (DTG), a second-generation integrase strand-transfer inhibitor (INSTI), is equivalent or superior to current non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and first-generation INSTI-based antiretroviral regimens (ARVs). It has the potential to make big improvements in HIV control globally and within patients. This is perhaps the most "precious" HIV drug available. The integrase mutation R263K has been observed in tissue culture experiments an...
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