Enfuvirtide, an HIV-1 Fusion Inhibitor, for Drug-Resistant HIV Infection in North and South America

Lalezari, Jacob; Henry, Keith; O'Hearn, Mary; Montaner, Julio S. G.; Piliero, Peter J.; Trottier, Benôit; Walmsley, Sharon; Cohen, Calvin; Kuritzkes, Daniel R.; Eron, Joseph J.; Chung, Jain; DeMasi, Ralph; Donatacci, Lucille; Drobnes, Claude; Delehanty, John; Salgo, Miklos

doi:10.1056/nejmoa035026

Cited by 845 publications

(585 citation statements)

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“…Currently, treatment for such diseases focuses on drugs and vaccines that specifically target the viral proteins or inhibit host-viral interactions 2,3 . However, the nature of lentiviral infections, whereby the virus, such as human immunodeficiency virus (HIV), invades immune cells and integrates into the host genome to establish its latent infection, has created a huge obstacle with respect to developing efficient vaccines 4,5 .…”

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confidence: 99%

Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in human cells

et al. 2015

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confidence: 99%

Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in human cells

et al. 2015

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“…Because of the persisting difficulties in developing a vaccine against HIV (1), the discovery of drugs to treat infected people and of prophylactic agents to prevent HIV infection remains a critical medical need. Despite considerable progress on this front, an increasing number of patients ultimately become resistant to highly-active antiretroviral therapy (HAART) because of the emergence of variants that are resistant to current treatment regimens (2). Moreover, patients may become infected with virus already resistant to multiple drugs (3), highlighting the need for continuous development of novel agents.…”

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confidence: 99%

Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency

Ingallinella

Bianchi

Ladwa

et al. 2009

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

188

247

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Peptides derived from the heptad repeat 2 (HR2) region of the HIV fusogenic protein gp41 are potent inhibitors of viral infection, and one of them, enfuvirtide, is used for the treatment of therapyexperienced AIDS patients. The mechanism of action of these peptides is binding to a critical intermediate along the virus-cell fusion pathway, and accordingly, increasing the affinity for the intermediate yields more potent inhibitors. We took a different approach, namely to increase the potency of the HR2 peptide inhibitor C34 by targeting it to the cell compartment where fusion occurs, and we show here that a simple, yet powerful way to accomplish this is attachment of a cholesterol group. C34 derivatized with cholesterol (C34-Chol) shows dramatically increased antiviral potency on a panel of primary isolates, with IC 90 values 15-to 300-fold lower than enfuvirtide and the second-generation inhibitor T1249, making C34-Chol the most potent HIV fusion inhibitor to date. Consistent with its anticipated mechanism of action, the antiviral activity of C34-Chol is unusually persistent: washing target cells after incubation with C34-Chol, but before triggering fusion, increases IC 50 only 7-fold, relative to a 400-fold increase observed for C34. Moreover, derivatization with cholesterol extends the half-life of the peptide in vivo. In the mouse, s.c. administration of 3.5 mg/kg C34-Chol yields a plasma concentration 24 h after injection >300-fold higher than the measured IC 90 values. Because the fusion machinery targeted by C34-Chol is similar in several other enveloped viruses, we believe that these findings may be of general utility. antiretroviral drug ͉ enveloped viruses ͉ lipid rafts ͉ peptide therapeutic

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“…Although several HIV-1 entry inhibitors have been evaluated in clinical trials and have shown promising prospects for therapy (1,28), the only entry inhibitor licensed to date is the fusion inhibitor enfuvirtide (ENF; also called T20), which has shown potent antiviral activity in patients, resulting in sustained viral load reduction when used in combination with an optimized background regimen of protease and/or reverse transcriptase inhibitors (21)(22)(23). Similar to results with other antiviral agents, however, ENF-resistant HIV-1 variants may emerge under the selective pressure of ENF (26,32,39,42) whenever the treatment fails to completely suppress viral replication in vivo.…”

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Role of the Envelope Genetic Context in the Development of Enfuvirtide Resistance in Human Immunodeficiency Virus Type 1-Infected Patients

Labrosse

Morand‐Joubert

Goubard

et al. 2006

J Virol

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Acquired human immunodeficiency virus type 1(HIV-1) resistance to the fusion inhibitor enfuvirtide (ENF)is primarily associated with mutations within the highly conserved first heptad repeat (HR1) region of gp41. Viral env sequences, however, are remarkably variable, and the envelope genetic background could have an important impact on optimal expression of HR1 mutations. We have examined the genetic evolution of env sequences, ENF susceptibility, and Env replicative capacity in patients failing ENF treatment. Sequential plasma-derived virus populations, obtained from six patients initiating ENF treatment as part of a salvage therapy, were studied using a recombinant phenotypic assay evaluating the entire gp120 and the gp41 ectodomains. Regardless of major differences in the baseline ENF susceptibilities, viral populations with similar phenotypic ENF resistance (50% inhibitory concentration, >3,000 ng/ml) were selected under treatment in four of six patients. As expected, in all patients ENF-resistant viruses harbored one or more HR1 mutations (positions 36, 38, and 43). Interestingly, in five patients the emergence of resistance mutations was not associated with reduced Env replicative capacity. Phylogenetic analysis of env sequences in sequential samples from two patients showed that the HR1 mutations had emerged in the context of env quasi-species that were different from those prevalent at baseline. Thus, the envelope genetic context appears to play a critical role in the selection of HR1 mutations and the expression of ENF resistance, thereby conditioning the evolution of HIV-1 under fusion inhibitor selective pressure.Considerable effort is currently being devoted to the development of antiviral agents able to prevent human immunodeficiency virus type 1 (HIV-1) entry into target cells. The HIV-1 entry process is mediated by the trimeric viral envelope glycoproteins (Env) exposed at the surface of the virion (45). The HIV-1 entry is a multistep process (11,14,45). The sequential interaction of the surface subunit, gp120, with CD4 and a chemokine receptor (CCR5 or CXCR4) exposed on the cell membrane triggers conformational changes in the ectodomain of the transmembrane subunit, gp41, which ultimately lead to fusion between the viral and host cell membranes. Like most of the retroviral transmembrane proteins, the ectodomain of gp41 contains an N-terminal fusion peptide followed by two heptad repeat domains (HR1 and HR2), which are connected by a non-helical loop region of 25 to 30 amino acids. Membrane fusion is currently thought to result from the insertion of the fusion peptide into the cellular membrane, and the formation of a six-helix bundle in which the central trimeric HR1 coiled-coil forms three hydrophobic grooves onto which three HR2 domains pack in reverse orientation (4,5,40,43).Although several HIV-1 entry inhibitors have been evaluated in clinical trials and have shown promising prospects for therapy (1, 28), the only entry inhibitor licensed to date is the fusion inhibitor enfuvirtide (ENF; als...

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Enfuvirtide, an HIV-1 Fusion Inhibitor, for Drug-Resistant HIV Infection in North and South America

Abstract: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.

Cited by 845 publications

References 15 publications

Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in human cells

Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in human cells

Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency

Role of the Envelope Genetic Context in the Development of Enfuvirtide Resistance in Human Immunodeficiency Virus Type 1-Infected Patients

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