Cross-resistance Profile of the Novel Integrase Inhibitor Dolutegravir (S/GSK1349572) Using Clonal Viral Variants Selected in Patients Failing Raltegravir

Canducci, Filippo; Ceresola, Elisa Rita; Boeri, Enzo; Spagnuolo, Vincenzo; Cossarini, Francesca; Castagna, Antonella; Lazzarin, Adriano; Clementi, Massimo

doi:10.1093/infdis/jir636

Cited by 88 publications

(70 citation statements)

References 10 publications

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“…Not all possible combinations were studied, as this would have been impossible. The E92Q T97A, E92Q Y143R, and G140S Q148R combinations were chosen as they are clinically relevant and confer resistance to DTG, EVG, and/or RAL in HIV-1 (40,(49)(50)(51)(52). We have also shown the effect of introducing single or double substitutions in the IN gene of SIVmac239 on viral infectivity and IN strand transfer and 3=-processing activity.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Hassounah

Liu

Quashie

et al. 2015

J Virol

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We previously showed that the simian immunodeficiency virus SIVmac239 is susceptible to human immunodeficiency virus (HIV) integrase (IN) strand transfer inhibitors (INSTIs) and that the same IN drug resistance mutations result in similar phenotypes in both viruses. Now we wished to determine whether tissue culture drug selection studies with SIV would yield the same resistance mutations as in HIV. Tissue culture selection experiments were performed using rhesus macaque peripheral blood mononuclear cells (PBMCs) infected with SIVmac239 viruses in the presence of increasing concentrations of dolutegravir (DTG), elvitegravir (EVG), and raltegravir (RAL). We now show that 22 weeks of selection pressure with DTG yielded a mutation at position R263K in SIV, similar to what has been observed in HIV, and that selections with EVG led to emergence of the E92Q substitution, which is a primary INSTI resistance mutation in HIV associated with EVG treatment failure. To study this at a biochemical level, purified recombinant SIVmac239 wild-type (WT) and E92Q, T97A, G118R, Y143R, Q148R, N155H, R263K, E92Q T97A, E92Q Y143R, R263K H51Y, and G140S Q148R recombinant substitution-containing IN enzymes were produced, and each of the characteristics strand transfer, 3=-processing activity, and INSTI inhibitory constants was assessed in cell-free assays. The results show that the G118R and G140S Q148R substitutions decreased K m = and V max =/K m = for strand transfer compared to those of the WT. RAL and EVG showed reduced activity against both viruses and against enzymes containing Q148R, E92Q Y143R, and G140S Q148R. Both viruses and enzymes containing Q148R and G140S Q148R showed moderate levels of resistance against DTG. This study further confirms that the same mutations associated with drug resistance in HIV display similar profiles in SIV. IMPORTANCEOur goal was to definitively establish whether HIV and simian immunodeficiency virus (SIV) share similar resistance pathways under tissue culture drug selection pressure with integrase strand transfer inhibitors and to test the effect of HIV-1 integrase resistance-associated mutations on SIV integrase catalytic activity and resistance to integrase strand transfer inhibitors. Clinically relevant HIV integrase resistance-associated mutations were selected in SIV in our tissue culture experiments. Not only do we report on the characterization of SIV recombinant integrase enzyme catalytic activities, we also provide the first research anywhere on the effect of mutations within recombinant integrase SIV enzymes on drug resistance.T he limitations of current highly active antiretroviral therapy (HAART) include the incidence of drug resistance observed in patients, issues of drug adherence, and numbers of newly acquired infections. The emergence of drug-resistant viruses can lead to increases in viral load and treatment failure, and such viruses can be transmitted to both healthy individuals as well as to untreated HIV-positive individuals, therefore threatening the long-term effica...

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Section: Discussionmentioning

confidence: 99%

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Hassounah

Liu

Quashie

et al. 2015

J Virol

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“…Although superior to raltegravir, it also exhibits significant resistance overlap. 8 It can therefore be stated that IN still remains an orphan in terms of marketable drugs and an attractive and scientifically challenging target. One of the most innovative strategies so far was the design of inhibitors targeting the Lens Epithelium Derived Growth Factor (LEDGF)/p75 binding site on integrase (LEDGINs).…”

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confidence: 99%

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

Billamboz

Suchaud

Bailly

et al. 2013

ACS Med. Chem. Lett.

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A series of 2-hydroxy-1,3-dioxoisoquinoline-4-carboxamides featuring an N-hydroxyimide chelating functionality was evaluated for their inhibitory properties against human immunodeficiency virus type 1 integrase (HIV-1 IN). Several derivatives displayed low nanomolar IC 50 values comparable to that of the clinically used raltegravir. A marked effect of one compound on both primary IN-catalyzed reactions, strand transfer (ST), and 3′ processing (3′-P), emphasizes a novel IN inhibition mechanism establishing it as a potential new generation IN inhibitor. Substitution of the 2-hydroxyisoquinoline-1,3-dione scaffold at position 4 by carboxamido chains was beneficial for antiviral activity since reproducible low micromolar anti-HIV activities were obtained for the first time within this scaffold.

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“…Twenty thousand TZM-bl cells/well were seeded in 96-well plates in complete DMEM supplemented with 30 g/ml DEAE-dextran (Sigma-Aldrich). Three hundred times the 50% tissue culture infective dose (TCID 50 )/ml of each strain was pretreated for 1 h at 37°C with six serial dilutions (range, 20.000 nM to 6.4 nM) of each compound and then added to the cells, as described previously (24,25). Vehicle (0.1% dimethyl sulfoxide [DMSO])-treated cells served as a negative control.…”

Section: Methodsmentioning

confidence: 99%

2-Aminothiazolones as Anti-HIV Agents That Act as gp120-CD4 Inhibitors

Tiberi

Tintori

Ceresola

et al. 2014

Antimicrob Agents Chemother

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eWe report here the synthesis of 2-aminothiazolones along with their biological properties as novel anti-HIV agents. Such compounds have proven to act through the inhibition of the gp120-CD4 protein-protein interaction that occurs at the very early stage of the HIV-1 entry process. No cytotoxicity was found for these compounds, and broad antiviral activities against laboratory strains and pseudotyped viruses were documented. Docking simulations have also been applied to predict the mechanism, at the molecular level, by which the inhibitors were able to interact within the Phe43 cavity of HIV-1 gp120. Furthermore, a preliminary absorption, distribution, metabolism, and excretion (ADME) evaluation was performed. Overall, this study led the basis for the development of more potent HIV entry inhibitors.

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Cross-resistance Profile of the Novel Integrase Inhibitor Dolutegravir (S/GSK1349572) Using Clonal Viral Variants Selected in Patients Failing Raltegravir

Cited by 88 publications

References 10 publications

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

2-Aminothiazolones as Anti-HIV Agents That Act as gp120-CD4 Inhibitors

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