Probing the Flavivirus Membrane Fusion Mechanism by Using Monoclonal Antibodies

Stiasny, Karin; Brandler, Samantha; Kössl, Christian; Heinz, Franz X.

doi:10.1128/jvi.01041-07

Cited by 46 publications

(41 citation statements)

References 33 publications

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“…Single-particle tracking studies suggest that virus entry occurs within 17 min of stable attachment of the virion (67). In vitro studies clearly demonstrate that viral fusion occurs very rapidly (within seconds) after exposure to mildly acidic conditions (58,66,76).…”

Section: Flavivirusesmentioning

confidence: 93%

“…1D); some strains of WNV are nonglycosylated (48,49). Neutralizing antibodies have been mapped to all three E protein domains and, in many instances, bind epitopes composed of residues from multiple domains (50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61). Antibodies that recognize prM have also been identified, but they have limited neutralization potential (53,(62)(63)(64).…”

Section: Flavivirusesmentioning

confidence: 99%

See 1 more Smart Citation

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

VanBlargan

Goo

Pierson

2016

Microbiol Mol Biol Rev

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SUMMARY The antibody response plays a key role in protection against viral infections. While antiviral antibodies may reduce the viral burden via several mechanisms, the ability to directly inhibit (neutralize) infection of cells has been extensively studied. Eliciting a neutralizing-antibody response is a goal of many vaccine development programs and commonly correlates with protection from disease. Considerable insights into the mechanisms of neutralization have been gained from studies of monoclonal antibodies, yet the individual contributions and dynamics of the repertoire of circulating antibody specificities elicited by infection and vaccination are poorly understood on the functional and molecular levels. Neutralizing antibodies with the most protective functionalities may be a rare component of a polyclonal, pathogen-specific antibody response, further complicating efforts to identify the elements of a protective immune response. This review discusses advances in deconstructing polyclonal antibody responses to flavivirus infection or vaccination. Our discussions draw comparisons to HIV-1, a virus with a distinct structure and replication cycle for which the antibody response has been extensively investigated. Progress toward deconstructing and understanding the components of polyclonal antibody responses identifies new targets and challenges for vaccination strategies.

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Section: Flavivirusesmentioning

confidence: 93%

Section: Flavivirusesmentioning

confidence: 99%

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

VanBlargan

Goo

Pierson

2016

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

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“…For DENV-3-E47, this was quite surprising as the neutralization potency was strong, with EC 50 values of ϳ110 ng/ml against the parent strain (Table 2). Due to the disparity between the EC 50 values and protection, the neutralization potential of DENV-3-E47, DENV-3-E48, and DENV-3-E52 was confirmed using the mouse-adapted 16652 strain; notably, no difference in EC 50 value from that for the parental virus was observed (data not shown). In comparison, 13 MAbs protected significantly, and these were separated into two (moderate-and high-level) groups.…”

Section: Vol 84 2010mentioning

confidence: 93%

Genotype-Specific Neutralization and Protection by Antibodies against Dengue Virus Type 3

Brien

Austin

Sukupolvi-Petty

et al. 2010

J Virol

134

153

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Dengue viruses (DENV) comprise a family of related positive-strand RNA viruses that infect up to 100 million people annually. Currently, there is no approved vaccine or therapy to prevent infection or diminish disease severity. Protection against DENV is associated with the development of neutralizing antibodies that recognize the viral envelope (E) protein. Here, with the goal of identifying monoclonal antibodies (MAbs) that can function as postexposure therapy, we generated a panel of 82 new MAbs against DENV-3, including 24 highly neutralizing MAbs. Using yeast surface display, we localized the epitopes of the most strongly neutralizing MAbs to the lateral ridge of domain III (DIII) of the DENV type 3 (DENV-3) E protein. While several MAbs functioned prophylactically to prevent DENV-3-induced lethality in a stringent intracranial-challenge model of mice, only three MAbs exhibited therapeutic activity against a homologous strain when administered 2 days after infection. Remarkably, no MAb in our panel protected prophylactically against challenge by a strain from a heterologous DENV-3 genotype. Consistent with this, no single MAb neutralized efficiently the nine different DENV-3 strains used in this study, likely because of the sequence variation in DIII within and between genotypes. Our studies suggest that strain diversity may limit the efficacy of MAb therapy or tetravalent vaccines against DENV, as neutralization potency generally correlated with a narrowed genotype specificity.Dengue viruses (DENV) cause the most common arthropod-borne viral infection in humans worldwide, with ϳ50 million to 100 million people infected annually and ϳ2.5 billion people at risk (13, 61). Infection by four closely related but serologically distinct viruses of the Flavivirus genus (DENV serotypes 1, 2, 3, and 4 [DENV-1 to -4, respectively]) cause dengue fever (DF), an acute, self-limiting, yet severe, febrile illness, or dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS), a potentially fatal syndrome characterized by vascular leakage and a bleeding diathesis. Specific treatment or prevention of dengue disease is supportive, as there is no approved antiviral therapy or vaccine available.DENV has an ϳ11-kb, single-stranded, positive-sense RNA genome that is translated into a polyprotein and is cleaved posttranslationally into three structural (envelope [E], pre/ membrane [prM], and capsid [C]) and seven nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins. The three structural proteins encapsidate a single infectious RNA of the DENV genome, whereas the nonstructural proteins have key enzymatic or regulatory functions that promote replication. Additionally, several DENV proteins are multifunctional and modulate cell-intrinsic and cell-extrinsic host immune responses (10).Most flavivirus-neutralizing antibodies recognize the structural E protein (reviewed in reference 40). Based on X-ray crystallographic analysis (32, 33), the DENV E protein is divided into three domains: domain I (DI), which is an 8-strand...

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“…However, a DII dimer interface MAb with more-similar properties for the distantly related flavivirus TBEV has been described ( Table 4). MAb A5 (26) maps to residue E207 along the dimer interface (45), is strongly neutralizing in culture (26), and partially blocks TBEV fusion in a pyrene excimer liposome fusion assay (74). Moreover, the binding of at least some cross-reactive neutralizing flavivirus MAbs (e.g., 4G2 and 6B6C-1) that map to the fusion peptide in DII are also affected by mutations of residues (E231) along a dimer interface (10).…”

Section: Discussionmentioning

confidence: 99%

Human Monoclonal Antibodies against West Nile Virus Induced by Natural Infection Neutralize at a Postattachment Step

Vogt¹,

Moesker

Goudsmit

et al. 2009

J Virol

105

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West Nile virus (WNV) is a neurotropic flavivirus that is now a primary cause of epidemic encephalitis inWNV cycles in nature between several species of birds and Culex mosquitoes, with humans and other mammals as deadend hosts (25, 62). Infection causes syndromes ranging from a mild febrile illness to severe encephalitis and death (13, 72). WNV has spread globally and causes outbreaks with thousands of severe human cases annually in the United States. An age of greater than 55 years, a compromised immune status, and a CC5⌬32 genotype have been associated with more-severe disease (15,20). There is currently no approved vaccine or therapy for WNV infection.The mature WNV virion has a ϳ500-Å diameter and consists of a single RNA genome surrounded by the capsid protein, a lipid bilayer, and a shell of the prM/M and E proteins (31, 55). X-ray crystallography studies have elucidated the three-domain structure of the flavivirus E protein (30,48,50,58,67). Domain I (DI) is a central, eight-stranded ␤-barrel, which contains the only N-linked glycosylation site in WNV E. Domain II (DII) is a long, finger-like protrusion from DI and contains the highly conserved fusion peptide at its distal end. Domain III (DIII) adopts an immunoglobulin-like fold at the opposite end of DI and is believed to contain a site for receptor attachment (6,8,40).Within an infected cell, progeny WNV are assembled initially as immature particles. In immature virions, three pairs of E and prM interact as trimers and form 60 spiked projections with icosahedral symmetry (85,86). Exposure to mildly acidic conditions in the trans-Golgi secretory pathway promotes virus maturation through a structural rearrangement of the E proteins and cleavage of prM to M by a furin-like protease (41,83). Mature WNV virions are covered by 90 antiparallel E protein homodimers, which are arranged flat along the surface in a herringbone pattern with quasi-icosahedral symmetry (55).Upon binding to poorly characterized cell surface receptors, internalization of WNV is believed to occur through receptormediated, clathrin-dependent endocytosis (1,79,80). After trafficking to 79), the mildly acidic pH within the lumen of the endosome induces structural alterations in the flavivirus E protein (7, 49), which includes changes in its oligomeric state (7,49,77). During this process, also known as type II fusion, the hydrophobic peptide on the fusion loop of DII of the E protein inserts into the

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Probing the Flavivirus Membrane Fusion Mechanism by Using Monoclonal Antibodies

Cited by 46 publications

References 33 publications

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

Genotype-Specific Neutralization and Protection by Antibodies against Dengue Virus Type 3

Human Monoclonal Antibodies against West Nile Virus Induced by Natural Infection Neutralize at a Postattachment Step

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