Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection

Cooper, David A.; Steigbigel, Roy T.; Gatell, José M.; Rockstroh, Jürgen K.; Katlama, Christine; Yéni, Patrick; Lazzarin, Adriano; Clotet, Bonaventura; Kumar, Princy; Eron, Joseph; Schechter, Mauro; Markowitz, Martin; Loutfy, Mona; Lennox, Jeffrey L.; Zhao, Jing; Chen, Joshua; Ryan, Desmon̄d; Rhodes, Rand R.; A., Killar, John; Gilde, Lucinda R.; Strohmaier, Kim M.; Meibohm, Anne R.; Miller, Michael D.; Hazuda, Daria J.; Nessly, Michael L.; DiNubile, Mark J.; Isaacs, Robin; Teppler, Hedy; Nguyen, Bach Yen

doi:10.1056/nejmoa0708978

Cited by 476 publications

(435 citation statements)

References 15 publications

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“…However, they all have limitations in routine clinical practice: integrase inhibitors are somewhat prone to lose efficacy due to resistance development 25 , enfuvirtide requires injection, and CCR5 antagonists are only active against R5 strains of virus. Thus, in patients who have experienced virologic failure of the three original classes it is uncertain whether these new classes will then be able to ensure lifelong viral suppression.…”

Section: Discussionmentioning

confidence: 99%

Triple-Class Virologic Failure in HIV-Infected Patients Undergoing Antiretroviral Therapy for Up to 10 Years

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Lodwick²,

Costagliola³

et al. 2010

Archives of Internal Medicine

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Section: Discussionmentioning

confidence: 99%

Triple-Class Virologic Failure in HIV-Infected Patients Undergoing Antiretroviral Therapy for Up to 10 Years

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Lodwick²,

Costagliola³

et al. 2010

Archives of Internal Medicine

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“…Selection for resistance to the action of strand transfer inhibitors has been shown to map to the integrase gene and to encode changes near the catalytic triad responsible for catalytic activity (16,38). Such changes have also been observed in the clinic to raltegravir, the first HIV integrase approved for treatment of HIV-infected patients (15). We performed biochemical experiments to characterize eight variants and also compared the results using isogenic viruses containing these resistance substitutions.…”

Section: Discussionmentioning

confidence: 99%

“…HIV integrase strand transfer inhibitors (STIs), which selectively target the strand transfer activity of integrase, possess potent anti-HIV activity in cell culture (11)(12)(13)(14), and the first one, raltegravir (15), has been approved for use in treatment experienced patients. Replication of HIV in the presence of increasing concentrations of STIs selects for resistant viruses, with amino acid changes within the integrase coding region (11,16).…”

Section: Hiv-1mentioning

confidence: 99%

Biochemical Analysis of HIV-1 Integrase Variants Resistant to Strand Transfer Inhibitors

Dicker

Terry

Lin

et al. 2008

Journal of Biological Chemistry

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In this study, eight different HIV-1 integrase proteins containing mutations observed in strand transfer inhibitor-resistant viruses were expressed, purified, and used for detailed enzymatic analyses. All the variants examined were impaired for strand transfer activity compared with the wild type enzyme, with relative catalytic efficiencies (k p /K m ) ranging from 0.6 to 50% of wild type. The origin of the reduced strand transfer efficiencies of the variant enzymes was predominantly because of poorer catalytic turnover (k p ) values. However, smaller secondorder effects were caused by up to 4-fold increases in K m values for target DNA utilization in some of the variants. All the variants were less efficient than the wild type enzyme in assembling on the viral long terminal repeat, as each variant required more protein than wild type to attain maximal activity. In addition, the variant integrases displayed up to 8-fold reductions in their catalytic efficiencies for 3-processing. The Q148R variant was the most defective enzyme. The molecular basis for resistance of these enzymes was shown to be due to lower affinity binding of the strand transfer inhibitor to the integrase complex, a consequence of faster dissociation rates. In the case of the Q148R variant, the origin of reduced compound affinity lies in alterations to the active site that reduce the binding of a catalytically essential magnesium ion. Finally, except for T66I, variant viruses harboring the resistance-inducing substitutions were defective for viral integration.

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“…Viral replication was measured by p24 gag ELISA for accumulation of viral particles in conditioned media. As shown in (24). Intrigued by these studies, we characterized the effects of SCFAs on HIV-1 replication in MDMs in the presence of raltegravir.…”

Section: Efficient Replication Of Episomal Hiv-1 In Primary Monocyte-mentioning

confidence: 95%

Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection

Kantor

Webster‐Cyriaque

et al. 2009

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

112

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Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection

Cited by 476 publications

References 15 publications

Triple-Class Virologic Failure in HIV-Infected Patients Undergoing Antiretroviral Therapy for Up to 10 Years

Triple-Class Virologic Failure in HIV-Infected Patients Undergoing Antiretroviral Therapy for Up to 10 Years

Biochemical Analysis of HIV-1 Integrase Variants Resistant to Strand Transfer Inhibitors

Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection

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