Identification of a Key Target Sequence To Block Human Immunodeficiency Virus Type 1 Replication within the
            <i>gag-pol</i>
            Transframe Domain

Sei, Shizuko; Yang, Quan en; O’Neill, Dennis; Yoshimura, Kazuhisa; Nagashima, Kunio; Mitsuya, Hiroaki

doi:10.1128/jvi.74.10.4621-4633.2000

Cited by 45 publications

(20 citation statements)

References 158 publications

(108 reference statements)

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“…8). This is the first report (58) have demonstrated that PNA targeted to the Gag-Pol transframe domain can arrest virus production. However, very high concentrations of PNA (100 M) were required to achieve this effect.…”

Section: Discussionmentioning

confidence: 99%

Anti-TAR Polyamide Nucleotide Analog Conjugated with a Membrane-Permeating Peptide Inhibits Human Immunodeficiency Virus Type 1 Production

Kaushik¹,

Basu²,

Palumbo

et al. 2002

J Virol

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The emergence of drug-resistant variants has posed a significant setback against effective antiviral treatment for human immunodeficiency virus (HIV) infections. The choice of a nonmutable region of the viral genome such as the conserved transactivation response element (TAR element) in the 5′ long terminal repeat (LTR) may potentially be an effective target for drug development. We have earlier demonstrated that a polyamide nucleotide analog (PNA) targeted to the TAR hairpin element, when transfected into cells, can effectively inhibit Tat-mediated transactivation of HIV type 1 (HIV-1) LTR (T. Mayhood et al., Biochemistry 39:11532-11539, 2000). Here we show that this anti-TAR PNA (PNATAR), upon conjugation with a membrane-permeating peptide vector (transportan) retained its affinity for TAR in vitro similar to the unconjugated analog. The conjugate was efficiently internalized into the cells when added to the culture medium. Examination of the functional efficacy of the PNATAR-transportan conjugate in cell culture using luciferase reporter gene constructs resulted in a significant inhibition of Tat-mediated transactivation of HIV-1 LTR. Furthermore, PNATAR-transportan conjugate substantially inhibited HIV-1 production in chronically HIV-1-infected H9 cells. The mechanism of this inhibition appeared to be regulated at the level of transcription. These results demonstrate the efficacy of PNATAR-transportan as a potential anti-HIV agent

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Section: Discussionmentioning

confidence: 99%

Anti-TAR Polyamide Nucleotide Analog Conjugated with a Membrane-Permeating Peptide Inhibits Human Immunodeficiency Virus Type 1 Production

Kaushik¹,

Basu²,

Palumbo

et al. 2002

J Virol

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“…HIV has been a frequent target for both RNAdegrading and steric-block approaches (Arzumanov et al, 2001b;Boulme et al, 1998;Darfeuille et al, 2002a;Darfeuille et al, 2004;Hiratou et al, 2001;Ittig et al, 2004;Kaushik et al, 2002;Park et al, 2000;Sei et al, 2000;Suzuki et al, 2002;Yamaguchi et al, 1997). For antisense technologies to become drug candidates, sequence specificity is essential.…”

confidence: 99%

Inhibition of HIV-1 Replication by Oligonucleotide Analogues Directed to the Packaging Signal and Trans-Activating Response Region

Brown

Arzumanov

Syed

et al. 2006

Antivir Chem Chemother

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HIV possesses a remarkable capacity for mutational escape from therapeutics that target the viral proteins and enzymes. Inhibitory strategies aimed at highly conserved nucleic acid sequences within the genome are an attractive alternative. However, it has proven difficult to achieve an effective level of therapeutic at the appropriate site within the cell. Oligonucleotide delivery is a rapidly advancing field. We have investigated oligonucleotide analogues as steric-block therapeutics against two highly conserved regions of the HIV-1 genome. In the study we show that 2'O-methyl/locked nucleic acid oligonucleotides against the packaging signal and trans-activating response regions of HIV can inhibit replication of the virus.

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“…Subconfluent COS-7 cells were transfected with 2 g of the pNL4-3 or APP/SPT clones in six-well plates. Efficiency of particle release was determined by measurement of HIV-1 p24 antigen enzyme-linked immunosorbent assay (ELISA) (Abbott, North Chicago, Ill.) in supernatant at 7,9,19,24,30,41, and 45 h posttransfection.…”

Section: Analysis Of P1-p6mentioning

confidence: 99%

Resistance to Nucleoside Analog Reverse Transcriptase Inhibitors Mediated by Human Immunodeficiency Virus Type 1 p6 Protein

Peters

Muñoz

Yerly

et al. 2001

J Virol

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Resistance of human immunodeficiency virus type 1 (HIV-1) to antiretroviral agents results from target gene mutation within the pol gene, which encodes the viral protease, reverse transcriptase (RT), and integrase. We speculated that mutations in genes other that the drug target could lead to drug resistance. For this purpose, the p1-p6 gag -p6 pol region of HIV-1, placed immediately upstream of pol, was analyzed. This region has the potential to alter Pol through frameshift regulation (p1), through improved packaging of viral enzymes (p6 Gag ), or by changes in activation of the viral protease (p6 Pol ). Duplication of the proline-rich p6 Gag PTAP motif, necessary for late viral cycle activities, was identified in plasma virus from 47 of 222 (21.2%) patients treated with nucleoside analog RT inhibitor (NRTI) antiretroviral therapy but was identified very rarely from drugnaïve individuals. Molecular clones carrying a 3-amino-acid duplication, APPAPP (transframe duplication SPTSPT in p6 Pol ), displayed a delay in protein maturation; however, they packaged a 34% excess of RT and exhibited a marked competitive growth advantage in the presence of NRTIs. This phenotype is reminiscent of the inoculum effect described in bacteriology, where a larger input, or a greater infectivity of an organism with a wild-type antimicrobial target, leads to escape from drug pressure and a higher MIC in vitro. Though the mechanism by which the PTAP region participates in viral maturation is not known, duplication of this proline-rich motif could improve assembly and packaging at membrane locations, resulting in the observed phenotype of increased infectivity and drug resistance.Currently available combination antiretroviral therapy fails to achieve optimal suppression of viral replication in 20 to 45% of patients (21). A leading factor for failure is the development of resistance by mutation within the pol gene, encoding the viral reverse transcriptase (RT) and protease, which are the targets of currently used antiretroviral agents. In general, initial or primary mutations modify the active sites of these viral enzymes, followed by stepwise accumulation of secondary or compensatory mutations leading to restored enzyme functionality (5, 13).Given the extreme plasticity of the human immunodeficiency virus type 1 (HIV-1) genome, we speculated that genetic changes at a distance could contribute to the process of drug resistance. For this purpose, we analyzed the p1-p6 gag -p6 pol

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Identification of a Key Target Sequence To Block Human Immunodeficiency Virus Type 1 Replication within the gag-pol Transframe Domain

Cited by 45 publications

References 158 publications

Anti-TAR Polyamide Nucleotide Analog Conjugated with a Membrane-Permeating Peptide Inhibits Human Immunodeficiency Virus Type 1 Production

Anti-TAR Polyamide Nucleotide Analog Conjugated with a Membrane-Permeating Peptide Inhibits Human Immunodeficiency Virus Type 1 Production

Inhibition of HIV-1 Replication by Oligonucleotide Analogues Directed to the Packaging Signal and Trans-Activating Response Region

Resistance to Nucleoside Analog Reverse Transcriptase Inhibitors Mediated by Human Immunodeficiency Virus Type 1 p6 Protein

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