Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants

Kobayashi, Masanori; Nakahara, Koichiro; Seki, Takahiro; Miki, Shigeru; Kawauchi, Shinobu; Suyama, Akemi; Wakasa-Morimoto, Chiaki; Kodama, Makoto; Endoh, Takeshi; Oosugi, Eiichi; Matsushita, Yoshihiro; Murai, Hitoshi; Fujishita, Toshio; Yoshinaga, Tomokazu; Garvey, Edward P.; Foster, Scott A.; Underwood, Mark; Johns, Brian A.; Sato, Akihiko; Fujiwara, Tamio

doi:10.1016/j.antiviral.2008.06.012

Cited by 100 publications

(89 citation statements)

References 18 publications

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“…Resistance to RAL arises through one of three genetic pathways, Y143H/R/C, Q148H/R/K, or N155H (5), and substitutions at Gln148 confer significant cross-resistance to EVG (16). To start, an ex vivo infection assay (17) was calibrated to wide-ranging INSTI sensitivities by determining the 50% effective concentrations (EC 50 s) and EC 95 doses of RAL and EVG using the wild-type (WT) IN and the Q148H, G140S, and Q148H/G140S mutants constructed in HIV-1 NLX.Luc.RϪ , a single-round strain that expresses firefly luciferase from the HIV-1 NL4-3 nef position (22).…”

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confidence: 99%

“…2). To facilitate interpretation, residues that when altered can contribute to HIV-1 resistance were color coded green, and amino acid differences known to confer resistance, magenta (9,16,24,40); gray represents changes whose contributions to drug resistance are unknown. BIV IN carries His at the position corresponding to Asn155 in HIV-1 IN, perhaps contributing to its 23-fold-reduced sensitivity to RAL (Fig.…”

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Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Koh

Matreyek

Engelman

2011

J Virol

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Integrase inhibitors are emerging anti-human immunodeficiency virus (HIV) drugs, and multiple retroviruses and transposable elements were evaluated here for susceptibilities to raltegravir (RAL) and elvitegravir (EVG). All viruses, including primate and nonprimate lentiviruses, a Betaretrovirus, a Gammaretrovirus, and the Alpharetrovirus Rous sarcoma virus (RSV), were susceptible to inhibition by RAL. EVG potently inhibited all lentiviruses and intermediately inhibited Betaretrovirus and Gammaretrovirus infections yet was basically ineffective against RSV. Substitutions based on HIV type 1 (HIV-1) resistance changes revealed that integrase residue Ser150 contributed significantly to the resistance of RSV. The drugs intermediately inhibited intracisternal A-particle retrotransposition but were inactive against Sleeping Beauty transposition and long interspersed nucleotide element 1 (LINE-1) retrotransposition.Reverse transcription of retroviral RNA yields linear viral DNA (vDNA) containing a copy of the long terminal repeat (LTR) at each end. Integrase (IN) is an essential retroviral enzyme that catalyzes two reactions to insert the vDNA into cellular chromosomal DNA. IN prepares the LTR ends by hydrolyzing phosphodiester bonds adjacent to invariant CA dinucleotides, yielding reactive 3Ј deoxyadenylate (dA OH ) termini. In the nucleus, IN catalyzes DNA strand transfer by using the 3Ј OHs to cut the chromosome in a staggered fashion, concomitantly joining the vDNA ends to 5Ј phosphates. Hostmediated repair of the resulting DNA recombination intermediate completes the integration process. See reference 8 for an overview of retroviral reverse transcription and integration.IN belongs to the polynucleotidyl transferase superfamily of nucleic acid-metabolizing enzymes (7). Conserved amino acid residues (typically Asp and Glu [32]) arranged commonly on an RNase H structural fold comprise active sites that coordinate divalent metal ions for in-line nucleophilic attack of phosphodiester bonds. Due to its critical role in replication, human immunodeficiency virus type 1 (HIV-1) IN has long been targeted for drug development, and the first-in-class inhibitor raltegravir (RAL) was licensed in 2007 (45). Because RAL and related compounds preferentially inhibit DNA strand transfer activity, the drugs are referred to as IN strand transfer inhibitors (INSTIs) (24). Elvitegravir (EVG) is another well-studied INSTI (41). Recently determined X-ray crystal structures revealed that the drugs work by ejecting the 3Ј dA and its associated OH nucleophile from the IN active site (10,

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Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Koh

Matreyek

Engelman

2011

J Virol

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“…Moreover, in the course of development of the next generation of antiviral drugs, it is the only available approach (6,18). However, the concern remains whether virulence determinants identified through serial-passage experiments accurately represent those evolving naturally in the virus of interest (18). Few, if any, viral systems have direct comparisons of adaptive responses to the same selection pressure in nature versus laboratory settings in the same host.…”

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“…The experimental approach has great advantages as the settings and selection pressures are controlled and allow for repeatability and statistical analysis. Moreover, in the course of development of the next generation of antiviral drugs, it is the only available approach (6,18). However, the concern remains whether virulence determinants identified through serial-passage experiments accurately represent those evolving naturally in the virus of interest (18).…”

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Experimental Adaptation of an RNA Virus Mimics Natural Evolution

Hajimorad

Wen

Eggenberger

et al. 2011

J Virol

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Identification of virulence determinants of viruses is of critical importance in virology.In search of such determinants, virologists traditionally utilize comparative genomics between a virulent and an avirulent virus strain and construct chimeras to map their locations. Subsequent comparison reveals sequence differences, and through analyses of site-directed mutants, key residues are identified. In the absence of a naturally occurring virulent strain, an avirulent strain can be functionally converted to a virulent variant via an experimental evolutionary approach. However, the concern remains whether experimentally evolved virulence determinants mimic those that have evolved naturally. To provide a direct comparison, we exploited a plant RNA virus, soybean mosaic virus (SMV), and its natural host, soybean. Through a serial in vivo passage experiment, the molecularly cloned genome of an avirulent SMV strain was converted to virulent variants on functionally immune soybean genotypes harboring resistance factor(s) from the complex Rsv1 locus. Several of the experimentally evolved virulence determinants were identical to those discovered through a comparative genomic approach with a naturally evolved virulent strain. Thus, our observations validate an experimental evolutionary approach to identify relevant virulence determinants of an RNA virus.

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HIV Integrase

Johns

2010

Burger's Medicinal Chemistry and Drug Discovery

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Integrase (IN) is one of only three viral enzymes encoded by the human immunodeficiency virus (HIV). The enzymatic activity of IN catalyzes the “integration” of viral double‐stranded DNA into host chromatin. Several steps including assembly, nuclear import, and gap repair are involved in the overall integration process, but two distinct biochemical steps are catalyzed by IN. The first step called 3′ processing allows for water to cleave the terminal dinucleotide on the respective ends of the viral DNA. The second discreet step called strand transfer facilitates the nicking of the host DNA by the recessed 3′ hydroxyl groups of the processed viral DNA. It is this second step of strand transfer that has been the focus of the bulk share of drug discovery efforts to date and the only step successfully inhibited by compounds that all fall into a class called two‐metal chelators. The science around the integrase enzyme is presented from a high‐level view of integration as part of the retroviral replication cycle through a molecular view of the biochemistry of the integration process involving nucleic acid strands. This chapter discusses inhibition of the strand transfer process and presents the two‐metal pharmacophore model and inhibitor design. The body of this work is focused on numerous classes of two‐metal chelation inhibitors of HIV‐1 integrase including several clinical candidates. The chapter concludes with a short survey of potential next‐generation compounds that have appeared in the literature through the end of 2008.

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Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants

Cited by 100 publications

References 18 publications

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Experimental Adaptation of an RNA Virus Mimics Natural Evolution

HIV Integrase

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