Efficacy of Enfuvirtide in Patients Infected with Drug-Resistant HIV-1 in Europe and Australia

Lazzarin, Adriano; Clotet, Bonaventura; Cooper, David A.; Reynes, Jacques; Arastéh, Keikawus; Nelson, Mark; Katlama, Christine; Stellbrink, Hans Jürgen; Delfraissy, Jean François; Lange, Joep M. A.; Huson, Les; DeMasi, Ralph; Wat, Cynthia; Delehanty, John; Drobnes, Claude; Salgo, Miklos

doi:10.1056/nejmoa035211

Cited by 602 publications

(408 citation statements)

References 14 publications

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“…We employed a second type of cell-cell fusion assay that makes it possible to measure the rate as well as extent of membrane fusion (34). In this assay, cells expressing CD4 and CCR5 are loaded with the fluorescent dye CCF2-AM, after which they are mixed with cells expressing the desired Env protein as well as ␤-lactamase.…”

Section: Resultsmentioning

confidence: 99%

“…The development of a new class of antiviral agents that prevent entry of HIV into cells is a promising prospect for therapy, as viruses resistant to reverse transcriptase and protease inhibitors remain sensitive to these compounds (38,39). Indeed, addition of the recently licensed entry inhibitor enfuvirtide (also called T-20 and Fuzeon) to an optimized background regimen of reverse transcriptase and protease inhibitors results in an average 10-fold reduction in viral load, which in many cases is sustained over a prolonged time period (32)(33)(34). Entry inhibitors described to date block binding of the viral envelope (Env) protein to CD4, binding of Env to the coreceptor, or the membrane fusion reaction itself (20,38).…”

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confidence: 99%

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Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

Reeves

Miamidian

Biscone

et al. 2004

J Virol

106

111

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An increasingly large number of antiviral agents that prevent entry of human immunodeficiency virus (HIV) into cells are in preclinical and clinical development. The envelope (Env) protein of HIV is the major viral determinant that affects sensitivity to these compounds. To understand how changes in Env can impact entry inhibitor sensitivity, we introduced six mutations into the conserved coreceptor binding site of the R5 HIV-1 strain YU-2 and measured the effect of these changes on CD4 and coreceptor binding, membrane fusion levels and rates, virus infection, and sensitivity to the fusion inhibitors enfuvirtide (T-20) and T-1249, the CCR5 inhibitor TAK-779, and an antibody to CD4. The mutations had little effect on CD4 binding but reduced CCR5 binding to various extents. In general, reductions in coreceptor binding efficiency resulted in slower fusion kinetics and increased sensitivity to TAK-779 and enfuvirtide. In addition, low CCR5 binding usually reduced overall fusion and infection levels. However, one mutation adjacent to the bridging sheet ␤21 strand, P438A, had little effect on fusion activity, fusion rate, infectivity, or sensitivity to enfuvirtide or T-1249 despite causing a marked reduction in CCR5 binding and a significant increase in TAK-779 sensitivity. Thus, our findings indicate that changes in the coreceptor binding site of Env can modulate its fusion activity, infectivity, and entry inhibitor sensitivity by multiple mechanisms and suggest that reductions in coreceptor binding do not always result in prolonged fusion kinetics and increased sensitivity to enfuvirtide.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

Reeves

Miamidian

Biscone

et al. 2004

J Virol

106

111

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“…We are focusing our efforts on eliciting neutralizing antibodies that target a transient viral entry intermediate. Earlier studies have shown that this transient intermediate, referred to as the prehairpin intermediate, can be targeted by peptide inhibitors that prevent HIV-1 infection in vitro (6) and in human patients (7).…”

mentioning

confidence: 99%

Vaccination with peptide mimetics of the gp41 prehairpin fusion intermediate yields neutralizing antisera against HIV-1 isolates

Bianchi¹,

Joyce²,

Miller

et al. 2010

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

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Eliciting a broadly neutralizing polyclonal antibody response against HIV-1 remains a major challenge. One approach to vaccine development is prevention of HIV-1 entry into cells by blocking the fusion of viral and cell membranes. More specifically, our goal is to elicit neutralizing antibodies that target a transient viral entry intermediate (the prehairpin intermediate) formed by the HIV-1 gp41 protein. Because this intermediate is transient, a stable mimetic is required to elicit an immune response. Previously, a series of engineered peptides was used to select a mAb (denoted D5) that binds to the surface of the gp41 prehairpin intermediate, as demonstrated by x-ray crystallographic studies. D5 inhibits the replication of HIV-1 clinical isolates, providing proof-of-principle for this vaccine approach. Here, we describe a series of peptide mimetics of the gp41 prehairpin intermediate designed to permit a systematic analysis of the immune response generated in animals. To improve the chances of detecting weak neutralizing polyclonal responses, two strategies were employed in the initial screening: use of a neutralization-hypersensitive virus and concentration of the IgG fraction from immunized animal sera. This allowed incremental improvements through iterative cycles of design, which led to vaccine candidates capable of generating a polyclonal antibody response, detectable in unfractionated sera, that neutralize tier 1 HIV-1 and simian HIV primary isolates in vitro. Our findings serve as a starting point for the design of more potent immunogens to elicit a broadly neutralizing response against the gp41 prehairpin intermediate.

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“…Asano et al determined that conjugation of a linker, which replaces the difluorocyclohexyl group results in an efficacy which was 2 orders of magnitude lower than the parental maraviroc. [91] By contrast, addition of a linker on the triazole ring resulted in a potent maraviroc derivative which was further modified with PEG5k and PEG40k yielding conjugates (36) that were %30-fold less effective in neutralizing HIV-1 JRFL than unmodified maraviroc (IC 50 ¼ 1.6 AE 0.25 Â 10 À9 M).…”

Section: Polymer Conjugated Entry and Fusion Inhibitorsmentioning

confidence: 99%

Polymeric Anti‐HIV Therapeutics

Danial

Klok

2014

Macromolecular Bioscience

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The scope of this review is to highlight the application of polymer therapeutics in an effort to curb the transmission and infection of the human immunodeficiency virus (HIV). Following a description of the HIV life cycle, the use of approved antiretroviral drugs that inhibit critical steps in the HIV infection process is highlighted. After that, a comprehensive overview of the structure and inhibitory properties of polymeric anti‐HIV therapeutic agents is presented. This overview will include inhibitors based on polysaccharides, synthetic polymers, dendritic polymers, polymer conjugates as well as polymeric DC‐SIGN antagonists. The review will conclude with a section that discusses the applications of polymers and polymer conjugates as systemic and topical anti‐HIV therapeutics.

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Efficacy of Enfuvirtide in Patients Infected with Drug-Resistant HIV-1 in Europe and Australia

Cited by 602 publications

References 14 publications

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

Vaccination with peptide mimetics of the gp41 prehairpin fusion intermediate yields neutralizing antisera against HIV-1 isolates

Polymeric Anti‐HIV Therapeutics

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