Rapid Emergence of Enfuvirtide Resistance in HIV-1-Infected Patients

Lü, Jing; Deeks, Steven G.; Hoh, Rebecca; Beatty, George; Kuritzkes, Benjamin; Martin, Jeffrey N.; Kuritzkes, Daniel R.

doi:10.1097/01.qai.0000234083.34161.55

Cited by 99 publications

(85 citation statements)

References 17 publications

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“…ENF prevents this interaction and so provides a strong selective pressure for mutations in its binding site in the HR-1 domain (5, 10). However, mutations in HR-1 that prevent ENF binding are likely to impact the binding of the HR-2 domain as well, reducing the efficiency of membrane fusion (9,12,15,18,20,22,27,29,30,32). Indeed, when mutations that confer ENF resistance (19) are introduced into HR-1, membrane fusion kinetics are delayed, there is enhanced sensitivity to neutralizing antibodies that bind to the membrane-proximal region in gp41 (28), and virus fitness is reduced as measured by in vitro assays (19).…”

Section: Discussionmentioning

confidence: 99%

“…Resistance to ENF results mostly or entirely from mutations in the ENF binding site in the HR-1 region of gp41 (9,12,15,18,20,22,29,30,32). In a previous report, we characterized Env proteins derived from five treatment-experienced patients prior to ENF treatment and at a time on treatment after virologic failure (27).…”

Section: Hr-2 Mutations Compensate For the Hr-1-induced Delay In Fusimentioning

confidence: 99%

“…Resistance to ENF, either in vivo or in vitro, is almost always associated with one or more mutations in the HR-1 region of gp41 (9,12,15,18,20,22,27,29,30,32). Presumably, these mutations impact the binding of ENF and hence its potency.…”

mentioning

confidence: 99%

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HR-2 Mutations in Human Immunodeficiency Virus Type 1 gp41 Restore Fusion Kinetics Delayed by HR-1 Mutations That Cause Clinical Resistance to Enfuvirtide

Ray

Blackburn

Doms

2009

J Virol

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Enfuvirtide (ENF) prevents the entry of human immunodeficiency virus type 1 (HIV-1) into cells by binding to the HR-1 region of the viral envelope (Env) protein gp41 subunit. Resistance to ENF arises via mutations in the drug binding site in HR-1. In addition, HR-2 mutations are commonly observed in ENF-resistant Env proteins, though their role remains unclear. We explored the mechanistic basis for clinical resistance to ENF and the role of HR-2 mutations. Using panels of ENF resistance-associated mutants for two patients, we found that mutations in HR-1 slowed the fusion kinetics and that mutations in HR-2 restored fusion rates. We assessed the differences in the rates of fusion of these mutants from a temperature-arrested state and observed similar trends, suggesting that the step of delay occurs after coreceptor engagement. Sensitivity to neutralizing antibodies was unchanged by the HR-1 and HR-2 mutants in each panel. Since this result was in contrast to those of a previous in vitro analysis where enhanced sensitivity to neutralization was demonstrated for heterologous Envs with ENF resistance-associated HR-1 changes, we examined the context dependence of HR-1 and HR-2 mutations by transferring the mutations seen in one patient into the Env context of another. These studies revealed that some, but not all, HR-1 mutations, when placed out of context (i.e., in a patient Env where they did not originally arise), enhance sensitivity to neutralizing antibodies. However, in most cases, HR-1 mutations in ENF-treated patients evolve in a manner that preserves pretreatment neutralization sensitivity so as to evade the pressures of the immune system.

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Section: Discussionmentioning

confidence: 99%

Section: Hr-2 Mutations Compensate For the Hr-1-induced Delay In Fusimentioning

confidence: 99%

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HR-2 Mutations in Human Immunodeficiency Virus Type 1 gp41 Restore Fusion Kinetics Delayed by HR-1 Mutations That Cause Clinical Resistance to Enfuvirtide

Ray

Blackburn

Doms

2009

J Virol

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“…Enfuvirtide, however, is administered subcutaneously -in contrast to other antiretroviral drugs, which are administered orally -and can cause significant injection site reactions (Oldfield et al, 2005). Further, resistance to enfuvirtide may emerge rapidly in patients, but may be reversed upon cessation of enfuvirtide administration (Lu et al, 2006;Poveda et al, 2005). It is of importance, therefore, to identify treatment protocols that maximize enfuvirtide efficacy and/or minimize enfuvirtide-related side-effects.…”

Section: Introductionmentioning

confidence: 99%

Mechanism-based model of the pharmacokinetics of enfuvirtide, an HIV fusion inhibitor

Mohanty

Dixit

2008

Journal of Theoretical Biology

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We present a model of the pharmacokinetics of enfuvirtide, a potent inhibitor of the fusion of human immunodeficiency virus type 1 (HIV-1) with target cells. We assume that subcutaneously administered enfuvirtide accumulates in the injection region, diffuses locally, and gets absorbed into blood, where it reversibly associates with lipidic cell membranes and is eventually eliminated. We develop mathematical descriptions of each of these processes and predict the time-evolution of the concentration of enfuvirtide in plasma, C p . We find, interestingly, that diffusion of enfuvirtide in the subcutaneous region is decoupled from absorption, which enables deduction of analytical expressions for C p following single dose administration and ordinary differential equations following multiple dose administration and renders our model amenable to data analysis. Model predictions provide excellent fits to observed plasma concentration-time profiles of enfuvirtide following the intravenous and subcutaneous administration of a single dose and without any adjustable parameters capture quantitatively concentration-time profiles following the administration of multiple doses. Our model thus presents a robust description of the pharmacokinetics of enfuvirtide and may be applied in conjunction with models of viral dynamics to assess responses of HIV-1 patients to alternative enfuvirtide-based therapies. Further, our model reveals that key pharmacokinetic characteristics of enfuvirtide, viz., steady state values of peak and trough concentrations and area under the concentration-time curve, vary nearly linearly with dosage over a broad range of dosages and for different dosing regimens, which enables a priori estimation of enfuvirtide exposure levels for different treatment protocols and may serve to establish guidelines for therapy optimization.

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“…Enfurvirtide has antiviral activity similar to most other classes of antiretroviral drugs discussed above; however resistance develop rapidly in patients receiving the drug for salvage therapy who do not receive a sufficient number of RTI, PI and INI drugs such as efavirenz, lopinanir/r and raltegravir, respectively. The emergence of enfurvirtide resistant strains followed by virologic rebound has been observed in some patients within two to four weeks (Cabrera et al, 2006;Lu et al, 2006).…”

Section: Point Mutations Associated With Resistance To Fusion Inhibitorsmentioning

confidence: 99%

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

Khati¹,

Millroy²

2012

Point Mutation

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Rapid Emergence of Enfuvirtide Resistance in HIV-1-Infected Patients

Cited by 99 publications

References 17 publications

HR-2 Mutations in Human Immunodeficiency Virus Type 1 gp41 Restore Fusion Kinetics Delayed by HR-1 Mutations That Cause Clinical Resistance to Enfuvirtide

HR-2 Mutations in Human Immunodeficiency Virus Type 1 gp41 Restore Fusion Kinetics Delayed by HR-1 Mutations That Cause Clinical Resistance to Enfuvirtide

Mechanism-based model of the pharmacokinetics of enfuvirtide, an HIV fusion inhibitor

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

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