Resistance and cross-resistance with saquinavir and other HIV protease inhibitors

Roberts, Noel A.; Craig, Jane; Sheldon, Jonathan G.

doi:10.1097/00002030-199805000-00005

Cited by 91 publications

(69 citation statements)

References 18 publications

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“…This suggested that variant B3 is unable to completely inactivate ACp5, most likely because of a reduced catalytic efficacy. The decrease in catalytic activity of HIV protease as a consequence of mutations associated with resistance to inhibitors has been documented (9,22,23,30,42). As expected, when the transformants were plated on MacConkeymaltose medium supplemented with high concentrations of indinavir (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It should be possible to use this genetic test to identify, in HIV-infected patients undergoing HAART, viral clones that harbor protease variants resistant to a given inhibitor (3,7,16,41). The ability to detect, at a very early stage or even before initiation of an antiprotease treatment, the emergence of HIV variants resistant to given drugs should have major clinical benefits (9,27,30).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we show that this genetic test is able to distinguish between wild-type protease and inhibitor-resistant variants (5,11,25) that were isolated from patients undergoing highly active antiretroviral therapy (HAART). This approach could be used in phenotyping resistance tests to detect in AIDS patients preexisting or emerging minor subpopulations of viruses carrying antiprotease-resistant proteases (9,27,29,30).…”

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confidence: 99%

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Sensitive Genetic Screen for Protease Activity Based on a Cyclic AMP Signaling Cascade in Escherichia coli

et al. 2000

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We describe a genetic system that allows in vivo screening or selection of site-specific proteases and of their cognate-specific inhibitors in Escherichia coli. This genetic test is based on the specific proteolysis of a signaling enzyme, the adenylate cyclase (AC) of Bordetella pertussis. As a model system we used the human immunodeficiency virus (HIV) protease. When an HIV protease processing site, p5, was inserted in frame into the AC polypeptide, the resulting ACp5 protein retained enzymatic activity and, when expressed in an E. coli cya strain, restored the Cya ؉ phenotype. The HIV protease coexpressed in the same cells resulted in cleavage and inactivation of ACp5; the cells became Cya ؊ . When the entire HIV protease, including its adjacent processing sites, was inserted into the AC polypeptide, the resulting AC-HIV-Pr fusion protein, expressed in E. coli cya, was autoproteolysed and inactivated: the cells displayed Cya ؊ phenotype. In the presence of the protease inhibitor indinavir or saquinavir, AC-HIV-Pr autoproteolysis was inhibited and the AC activity of the fusion protein was preserved; the cells were Cya ؉ . Protease variants resistant to particular inhibitors could be easily distinguished from the wild type, as the cells displayed a Cya ؊ phenotype in the presence of these inhibitors. This genetic test could represent a powerful approach to screen for new proteolytic activities and for novel protease inhibitors. It could also be used to detect in patients undergoing highly active antiretroviral therapy the emergence of HIV variants harboring antiprotease-resistant proteases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Sensitive Genetic Screen for Protease Activity Based on a Cyclic AMP Signaling Cascade in Escherichia coli

et al. 2000

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“…For instance, HIV RT has an error rate of 1 mutation per 1,500 nucleotides, whereas RT of avian and murine origin generate 1 mutation per 17,000 and 30,000 nucleotides, respectively (Arezi and Hogrefe 2007;Roberts et al 1998).…”

Section: Reverse Transcriptase For Molecular Biologymentioning

confidence: 99%

Enzymes used in molecular biology: a useful guide

Rittié

Perbal

2008

Journal of Cell Communication and Signaling

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Since molecular cloning has become routine laboratory technique, manufacturers offer countless sources of enzymes to generate and manipulate nucleic acids. Thus, selecting the appropriate enzyme for a specific task may seem difficult to the novice. This review aims at providing the readers with some cues for understanding the function and specificities of the different sources of polymerases, ligases, nucleases, phosphatases, methylases, and topoisomerases used for molecular cloning. We provide a description of the most commonly used enzymes of each group, and explain their properties and mechanism of action. By pointing out key requirements for each enzymatic activity and clarifying their limitations, we aim at guiding the reader in selecting appropriate enzymatic source and optimal experimental conditions for molecular cloning experiments.

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“…The evolution of HIV toward high-level resistance to PI is thus the result of a gradual accumulation of those resistance mutations in the PR (58,59,96,253,258,311). Most of the HIV PR mutations associated with decreased sensitivity to PI have been identified, e.g., L10I, K20R, M36I, M46I, F53L, L63P, A71V, V82A, D30N, I84V, I54V, L90M, and G48V (58,59,143,167,234,237,290,291,312). These mutations are usually not found in HIV isolates which have not been previously exposed to PI (15,197,204,263,267,367).…”

Section: Emergence Of Resistant Mutantsmentioning

confidence: 99%

Positive and Negative Aspects of the Human Immunodeficiency Virus Protease: Development of Inhibitors versus Its Role in AIDS Pathogenesis

Ikuta

Suzuki

Horikoshi

et al. 2000

Microbiol Mol Biol Rev

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SUMMARY In this review we summarize multiple aspects of the human immunodeficiency virus (HIV) protease from both structural and functional viewpoints. After an introductory overview, we provide an up-to-date status report on protease inhibitors (PI). This proceeds from a discussion of PI structural design, to how PI are optimally utilized in highly active antiretroviral triple therapy (one PI along with two reverse transcriptase inhibitors), the emergence of PI resistance, and the natural role of secretory leukocyte PI. Then we switch to another focus: the interaction of HIV protease with other genes in acute and persistent infection, which in turn may have an effect on AIDS pathogenesis. We conclude with a discussion on future directions in HIV treatment, involving multiple-target anti-HIV therapy, vaccine development, and novel reactivation-inhibitory reagents.

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Resistance and cross-resistance with saquinavir and other HIV protease inhibitors

Cited by 91 publications

References 18 publications

Sensitive Genetic Screen for Protease Activity Based on a Cyclic AMP Signaling Cascade in Escherichia coli

Sensitive Genetic Screen for Protease Activity Based on a Cyclic AMP Signaling Cascade in Escherichia coli

Enzymes used in molecular biology: a useful guide

Positive and Negative Aspects of the Human Immunodeficiency Virus Protease: Development of Inhibitors versus Its Role in AIDS Pathogenesis

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