Fusion-Competent Vaccines: Broad Neutralization of Primary Isolates of HIV

LaCasse, Rachel; Follis, Kathryn E.; Trahey, Meg; Scarborough, John D.; Littman, Dan R.; Nunberg, Jack H.

doi:10.1126/science.283.5400.357

Cited by 204 publications

(104 citation statements)

References 45 publications

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“…In this study we have used immunogens in different combinations that contain the HIV-1 envelope gp120 and the transmembrane gp41 (gp160), a few gp41 peptides representing HIV-1-neutralizing regions, and the second external loop of the CCR5 receptor. It is known that the gp120 mediates binding and entry steps in HIV-1 infection and that the gp120-CD4 coreceptor binding induces conformational changes that activate the gp41 transmembrane regions of the envelope (32). It is also believed that the fusion structure of the envelope protein after CD4 and coreceptor binding breaks down into two coils within the gp41 monomer, and that synthetic peptides against either gp41 helical coil are able to inhibit viral infectivity (33,34).…”

Section: Discussionmentioning

confidence: 99%

Intranasal HIV-1-gp160-DNA/gp41 Peptide Prime-Boost Immunization Regimen in Mice Results in Long-Term HIV-1 Neutralizing Humoral Mucosal and Systemic Immunity

Devito

Zuber

Schröder³

et al. 2004

The Journal of Immunology

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An intranasal DNA vaccine prime followed by a gp41 peptide booster immunization was compared with gp41 peptide and control immunizations. Serum HIV-1-specific IgG and IgA as well as IgA in feces and vaginal and lung secretions were detected after immunizations. Long-term humoral immunity was studied for up to 12 mo after the booster immunization by testing the presence of HIV-1 gp41- and CCR5-specific Abs and IgG/IgA-secreting B lymphocytes in spleen and regional lymph nodes in immunized mice. A long-term IgA-specific response in the intestines, vagina, and lungs was obtained in addition to a systemic immune response. Mice immunized only with gp41 peptides and L3 adjuvant developed a long-term gp41-specific serum IgG response systemically, although over a shorter period (1–9 mo), and long-term mucosal gp41-specific IgA immunity. HIV-1-neutralizing serum Abs were induced that were still present 12 mo after booster immunization. HIV-1 SF2-neutralizing fecal and lung IgA was detectable only in the DNA-primed mouse groups. Intranasal DNA prime followed by one peptide/L3 adjuvant booster immunization, but not a peptide prime followed by a DNA booster, was able to induce B cell memory and HIV-1-neutralizing Abs for at least half of a mouse’s life span.

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Section: Discussionmentioning

confidence: 99%

Intranasal HIV-1-gp160-DNA/gp41 Peptide Prime-Boost Immunization Regimen in Mice Results in Long-Term HIV-1 Neutralizing Humoral Mucosal and Systemic Immunity

Devito

Zuber

Schröder³

et al. 2004

The Journal of Immunology

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“…Antibodies from vaccine trials using purified, native, full- length F protein have very low neutralizing activities compared with those generated by live HRSV (1). One suggested strategy for eliciting neutralizing HIV-1 antibodies is to target transient intermediates or fusion-competent conformations (39,43). The N-terminal coiled coil observed in the current structure might be formed in a prehairpin intermediate analogous to that found in HIV-1 and thus may be a viable target for antifusion antibodies.…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of the human respiratory syncytial virus fusion protein core

Zhao

Singh

Malashkevich

et al. 2000

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

266

259

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Human respiratory syncytial virus (HRSV) is a major cause of a number of severe respiratory diseases, including bronchiolitis and pneumonia, in infants and young children. The HRSV F protein, a glycoprotein essential for viral entry, is a primary target for vaccine and drug development. Two heptad-repeat regions within the HRSV F sequence were predicted by the computer program LEARN-COIL-VMF. These regions are thought to form trimer-of-hairpins-like structures, similar to those found in the fusion proteins of several enveloped viruses. The hairpin structure likely brings the viral and cellular membranes into close apposition, thereby facilitating membrane fusion and subsequent viral entry. Here, we show that peptides, denoted HR-N and HR-C, corresponding to the heptadrepeat regions from the N-terminal and C-terminal segments of the HRSV F protein, respectively, form a stable ␣-helical trimer of heterodimers. The HRSV N͞C complex was crystallized and its x-ray structure was determined at 2.3-Å resolution. As anticipated, the complex is a six-helix bundle in which the HR-N peptides form a three-stranded, central coiled coil, and the HR-C peptides pack in an antiparallel manner into hydrophobic grooves on the coiled-coil surface. There is remarkable structural similarity between the HRSV N͞C complex and the fusion protein core of other viruses, including HIV-1 gp41. In addition, earlier work has shown that HRSV HR-C peptides, like the HIV-1 gp41 C peptides, inhibit viral infection. Thus, drug discovery and vaccine development strategies aimed at inhibiting viral entry by blocking hairpin formation may be applied to the inhibition of HRSV.x-ray crystallography ͉ membrane fusion ͉ pneumovirus

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“…A search for compounds that prevent the pressure-induced effects may lead to agents capable of blocking formation of the FG state. A recent study (54) describes the potential of using fusion complexes for human immunodeficiency virus vaccine development. Since high pressure is able to produce fusion-intermediate states, which are similar to that at low pH in endosomes (alphaviruses and influenza virus) or that produced by binding to receptors (such as in human immunodeficiency virus), there is a great potential to utilize the pressure approach to produce vaccines.…”

Section: Fig 5 Pressure-induced Fusogenic State Of Sindbis Virusmentioning

confidence: 99%

Hydrostatic Pressure Induces the Fusion-active State of Enveloped Viruses

Gaspar¹,

Silva²,

Gomes³

et al. 2002

Journal of Biological Chemistry

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Enveloped animal viruses must undergo membrane fusion to deliver their genome into the host cell. We demonstrate that high pressure inactivates two membrane-enveloped viruses, influenza and Sindbis, by trapping the particles in a fusion-intermediate state. The pressure-induced conformational changes in Sindbis and influenza viruses were followed using intrinsic and extrinsic fluorescence spectroscopy, circular dichroism, and fusion, plaque, and hemagglutination assays. Influenza virus subjected to pressure exposes hydrophobic domains as determined by tryptophan fluorescence and by the binding of bis-8-anilino-1-naphthalenesulfonate, a well established marker of the fusogenic state in influenza virus. Pressure also produced an increase in the fusion activity at neutral pH as monitored by fluorescence resonance energy transfer using lipid vesicles labeled with fluorescence probes. Sindbis virus also underwent conformational changes induced by pressure similar to those in influenza virus, and the increase in fusion activity was followed by pyrene excimer fluorescence of the metabolically labeled virus particles. Overall we show that pressure elicits subtle changes in the whole structure of the enveloped viruses triggering a conformational change that is similar to the change triggered by low pH. Our data strengthen the hypothesis that the native conformation of fusion proteins is metastable, and a cycle of pressure leads to a final state, the fusion-active state, of smaller volume.Enveloped viruses utilize regulated membrane fusion to introduce their genomes in the cytoplasm of the host cell. The fusion is mediated by surface envelope proteins of the virus in response to a trigger (1, 2). Once triggered, the fusion process leads to a conformational change that promotes the interaction of a specific sequence (fusion peptide) with the target membrane and initiates membrane fusion. Membrane fusion is crucial in other biological functions such as myotube formation, fertilization, and trafficking of endocytic and exocytic vesicles within eukaryotic cells (1, 3). Many enveloped animal viruses have been studied as models for understanding the mechanism of membrane fusion. While the fusion proteins of many viruses reveal significant similarity in their putative fusogenic conformation, such as those of influenza virus (hemagglutinin HA2), 1 human immunodeficiency virus (gp41 protein), Moloney murine leukemia virus (TM protein), and Ebola virus (GP2 protein) (4), the events of membrane fusion for other virus families (e.g. Flaviviridae and Togaviridae) are beginning to be understood. Alphavirus and the flavivirus fusion proteins appear to have evolved from a common ancestor (5) and possess a similar new class of membrane fusion proteins that do not form coiledcoils (6 -8).Sindbis and influenza are enveloped viruses that first enter a cell by endocytosis and then fuse with the cellular membrane in response to acidic conditions. Sindbis virus is the prototype of the Alphavirus genus, Togaviridae family. The Alphavirus spike is...

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Fusion-Competent Vaccines: Broad Neutralization of Primary Isolates of HIV

Cited by 204 publications

References 45 publications

Intranasal HIV-1-gp160-DNA/gp41 Peptide Prime-Boost Immunization Regimen in Mice Results in Long-Term HIV-1 Neutralizing Humoral Mucosal and Systemic Immunity

Intranasal HIV-1-gp160-DNA/gp41 Peptide Prime-Boost Immunization Regimen in Mice Results in Long-Term HIV-1 Neutralizing Humoral Mucosal and Systemic Immunity

Structural characterization of the human respiratory syncytial virus fusion protein core

Hydrostatic Pressure Induces the Fusion-active State of Enveloped Viruses

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