Structural basis for HIV-1 neutralization by a gp41 fusion intermediate–directed antibody

Luftig, Micah A.; Mattu, Marco; Giovine, Paolo Di; Geleziunas, Romas; Hrin, Renee; Barbato, Gaetano; Bianchi, Elisabetta; Miller, Michael D.; Pessi, Antonello; Carfı́, Andrea

doi:10.1038/nsmb1127

Cited by 122 publications

(191 citation statements)

References 50 publications

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“…1) focused on residues 565-581 of the NHR (numbering according to HXB2 sequence), corresponding to the prominent hydrophobic pocket of the coiled-coil (11,20), which encompasses the D5 epitope (18,19). The chimeric mimetic IZN17 consists of an engineered trimerizing and solubilizing coiled-coil (denoted IZ) scaffold fused to aa 565-581 of gp41 (16).…”

Section: Resultsmentioning

confidence: 99%

“…The crystal structure of the Fab fragment of one of these mAbs (denoted D5) in complex with 5-helix (19) confirmed that D5 binds to the NHR region. Interestingly, D5 binds the same conserved hydrophobic pocket of the NHR trimer (20) that was previously shown to be the target of D-peptide (15) and peptidomimetic (21,22) HIV-1 fusion inhibitors.…”

mentioning

confidence: 87%

“…X-ray crystallographic studies show that D5 binds to the conserved hydrophobic pocket of the prehairpin intermediate (19). The concentration of antibodies capable of competing with D5 for the hydrophobic pocket region was measured by DCBA (Fig.…”

Section: Serological Analysis Of Animals Immunized With Nhr Peptidementioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 87%

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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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“…Such is indeed the case for C34, T20 (4), which spans part of the HR2 region and the sequence downstream (Fig. 1), and several other FI-targeting HR1 or HR2, including peptides, proteins, and small molecules (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

mentioning

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.

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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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“…2, the three antibodies were found to bind to all the prostate cells tested with comparable affinity even though Herceptin shows a lower binding ability on 22Rv1 and PC-3 cells. As a negative control, an unrelated human anti-HIV IgG1 antibody (27) was tested in parallel ELISA assays and was found unable to bind to the prostate cells (data not shown), mentioned above. As shown in Fig.…”

Section: Erbb2 Levels On Prostate Cancer Cellsmentioning

confidence: 99%

Effects of a human compact anti-ErbB2 antibody on prostate cancer

et al. 2012

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Abstract. Prostate cancer is the most commonly diagnosed malignancy in men in developed countries. ErbB2, a tyrosine kinase receptor overexpressed in many human cancer types, contributes to prostate cancer progression by activating the androgen receptor in a steroid poor environment, thus promoting androgen-independent cell growth. The consequent development of hormone refractory tumors is a major obstacle in prostate cancer therapy. The inhibition of ErbB2 signal transduction pathways by the use of human antibodies could be a valuable alternative strategy for cancer therapy. We performed a comparative analysis in vitro and in vivo of the antitumor effects of three different antibodies targeting different epitopes of ErbB2: Herceptin (trastuzumab), 2C4 (pertuzumab) and Erb-hcAb (human anti-ErbB2-compact antibody), a novel fully human compact antibody produced in our laboratory. Herein, we demonstrate that the growth of both androgen-dependent and independent prostate cancer cells was efficiently inhibited by Erb-hcAb. The antitumor effects induced by Erb-hcAb on some cell lines were more potent than those observed for either Herceptin or 2C4. Thus, Erb-hcAb could be a promising candidate in the immunotherapy of prostate cancer for which no obvious treatment has been reported so far.

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Structural basis for HIV-1 neutralization by a gp41 fusion intermediate–directed antibody

Cited by 122 publications

References 50 publications

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

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

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

Effects of a human compact anti-ErbB2 antibody on prostate cancer

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