Azido-Containing Diketo Acid Derivatives Inhibit Human Immunodeficiency Virus Type 1 Integrase In Vivo and Influence the Frequency of Deletions at Two-Long-Terminal-Repeat-Circle Junctions

Svarovskaia, Evguenia S.; Barr, Rebekah; Zhang, Xuechun; Pais, Godwin C. G.; Marchand, Christophe; Pommier, ﻿Yves; Burke, Terrence R.; Pathak, Vinay K.

doi:10.1128/jvi.78.7.3210-3222.2004

Cited by 97 publications

(98 citation statements)

References 68 publications

(82 reference statements)

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“…1B, green versus blue sequence numbers). It is also well established that integrase inhibitors of the diketo acid-derivative family, of which raltegravir is a member, increase the concentration of the preintegration (circular) cDNA up to 10-fold without affecting total viral cDNA synthesis (27,28). Similarly, in the presence of raltegravir, more MoMLV 2-LTR circles accumulated (Fig.…”

Section: Raltegravir Inhibits MLV Integration and Causes Accumulationmentioning

confidence: 95%

“…1B). However, in 20% of the cases in HIV 2-LTR circles, for example, one finds large deletions (28); the number of such deletions is increased in circles derived from MoMLV with a defective nucleocapsid protein (29). Of the seven sequences of MoMLV LTRs from NIH/3T3 cells shown in Fig.…”

Section: Trex1 Is Coresponsible For the Deletions At The Junctions Ofmentioning

confidence: 99%

“…All integrases have a characteristic catalytic core domain, the D,D35E motif (23)(24)(25)(26), and we found that the integration of MLV is also inhibited by raltegravir. Because integrase inhibitors are known to cause accumulation of retroviral preintegration DNA (27,28), they may exacerbate autoimmune disease, analogous to the effect in Trex1-deficient mice. Indeed, the activity profile of raltegravir for inhibition of MLV integration was similar to that for HIV, which led us to feed raltegravir to B/W and NZB mice, along with NZW and BALB/c mice as controls.…”

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confidence: 99%

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Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir

Beck-Engeser

Eilat²,

Harrer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Raltegravir is a recently, Food and Drug Administration-approved, small-molecule drug that inhibits retroviral integrase, thereby preventing HIV DNA from inserting itself into the human genome. We report here that the activity profile of raltegravir on the replication of murine leukemia virus is similar to that for HIV, and that the drug specifically affects autoimmune disease in mice, in which endogenous retroelements are suspected to play a role. While NZW and BALB/c mice, which do not succumb to autoimmune disease, are not affected by raltegravir, lupus-prone (NZBx-NZW) F 1 mice die of glomerulonephritis more than a month earlier than untreated mice. Raltegravir-treated NZB mice, which share the H-2 haplotype with BALB/c mice, but which are predisposed to autoimmune hemolytic anemia, develop auto-antibodies to their red blood cells >3 months earlier than untreated mice of the same strain. Because nonautoimmune mice are not affected by raltegravir, we consider off-target effects unlikely and attribute the exacerbation of autoimmunity to the inhibition of retroviral integrase.2-LTR circles ͉ hemolytic anemia ͉ lupus disease ͉ muring leukemia virus ͉ Trex1

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Section: Raltegravir Inhibits MLV Integration and Causes Accumulationmentioning

confidence: 95%

Section: Trex1 Is Coresponsible For the Deletions At The Junctions Ofmentioning

confidence: 99%

mentioning

confidence: 99%

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Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir

Beck-Engeser

Eilat²,

Harrer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…FITC-conjugated anti-CD4 mAb (clone RPA-T4) was purchased from eBioscience, PE-conjugated anti-CXCR4 mAb (clone 12G5) and PE-conjugated anti-CCR5 mAb (clone 5D7) from BD Biosciences, and the anti-GalCer mAb from Millipore. The following reagents were obtained through the AIDS Repository Reagent Program: EFV, a non-nucleoside reverse transcriptase inhibitor of HIV-1; 118-D-24, an integrase inhibitor (Svarovskaia et al, 2004); T-20, a fusion inhibitor; AMD-3100, an antagonist of CXCR4 (Bridger et al, 1995;De Clercq et al, 1994;Hendrix et al, 2000); and TAK-779, an antagonist of CCR5 (Baba et al, 1999).…”

Section: Methodsmentioning

confidence: 99%

Inefficient fusion due to a lack of attachment receptor/co-receptor restricts productive human immunodeficiency virus type 1 infection in human hepatoma Huh7.5 cells

Fromentin¹,

Tardif²,

Tremblay³

2010

Journal of General Virology

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“…The extracted DNAs were used in a real time PCR to quantitatively detect viral late reverse transcription product (U5-⌿) and cellular DNA. The late reverse transcription product U5-⌿ DNA was quantified as described previously (32,33). The following primer and probe sets were employed in the real time PCR assay to detect DNA products.…”

Section: Preparation Of Recombinant Wild Type and K244e Mutant Hiv-1mentioning

confidence: 99%

Mass Spectrometric Analysis of the HIV-1 Integrase-Pyridoxal 5′-Phosphate Complex Reveals a New Binding Site for a Nucleotide Inhibitor

Williams

Zhang

Shkriabai

et al. 2005

Journal of Biological Chemistry

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HIV-1 integrase (IN) is an important target for designing new antiviral therapies. Screening of potential inhibitors using recombinant IN-based assays has revealed a number of promising leads including nucleotide analogs such as pyridoxal 5-phosphate (PLP).The continuing emergence of new HIV-1 1 variants resistant to current therapeutic treatments, which include small molecule inhibitors targeting HIV-1 reverse transcriptase and protease, makes the search for new anti-HIV-1 drugs imperative. In this regard, HIV-1 integrase (IN), which has no known human counterparts, is an attractive target. Furthermore, the fact that IN uses a common active site for 3Ј-processing and DNA strand transfer may constrain the range of mutations that can contribute to evolution of viable drug-resistant viruses.HIV-1 IN catalyzes integration of the viral DNA, made by reverse transcription, into the host chromosome in a two-step reaction (reviewed in Ref. 1). In the first step, called 3Ј-processing, two nucleotides are removed at each 3Ј-end of the viral DNA. In the next step, called DNA strand transfer, concerted transesterification reactions integrate the viral DNA ends into the host genome.HIV-1 IN is composed of three distinct structural and functional domains: the N-terminal domain (residues 1-50) that contains the HHCC zinc-binding motif, the core domain (residues 51-212) that contains the catalytic site, and the C-terminal domain (residues 213-270) that is thought to provide a platform for DNA binding. Crystallographic or NMR structural data are available for each of the individual domains (2-6). In addition, the structures of the combined core and C-terminal domains (7) and core and N-terminal domains (8) have been recently determined. However, efforts to obtain a structure of the full-length protein have been impeded by poor protein solubility.Purified IN-based assays have been employed for screening of potential inhibitors. These studies have revealed several classes of compounds with anti-HIV-1 IN activity, including diketo acids, naphthyridines, pyranodipyrimidines, nucleotide analogs, hydroxylated aromatic compounds, DNA-interacting agents, peptides, and antibodies (9 -22). Much effort has been devoted to dissecting the mechanism of inhibition and identifying the inhibitor binding sites. Crystallographic studies revealed two distinct binding sites in IN including the catalytic site for a diketo group-containing inhibitor (1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)-propenone) and a site located near the IN dimer interface for 3,4-dihydroxyphenyltriphenylarsonium bromide (23,24). However, these studies employed the isolated core domain of IN rather then the fulllength protein.Mass spectrometry is a powerful structural biology tool that allows the analysis of protein-inhibitor complexes under biologically relevant conditions and provides structural information complementary to NMR and crystallography. For example, we recently reported identification of a small molecule inhibitor binding site to full-length IN using...

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Azido-Containing Diketo Acid Derivatives Inhibit Human Immunodeficiency Virus Type 1 Integrase In Vivo and Influence the Frequency of Deletions at Two-Long-Terminal-Repeat-Circle Junctions

Cited by 97 publications

References 68 publications

Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir

Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir

Inefficient fusion due to a lack of attachment receptor/co-receptor restricts productive human immunodeficiency virus type 1 infection in human hepatoma Huh7.5 cells

Mass Spectrometric Analysis of the HIV-1 Integrase-Pyridoxal 5′-Phosphate Complex Reveals a New Binding Site for a Nucleotide Inhibitor

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