In Vivo Selection of Respiratory Syncytial Viruses Resistant to Palivizumab

Zhao, Xiaodong; Sullender, Wayne M.

doi:10.1128/jvi.79.7.3962-3968.2005

Cited by 48 publications

(41 citation statements)

References 34 publications

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“…1D), Ile266 is positioned at the bottom of the antigenic site II helixloop-helix motif and is pointed toward the inner protein core, suggesting the residue disrupts the antigenic motif by allosteric effects. In the same study (11), selection with several murine mAbs produced MARM viruses with Lys272Asn, and similarly, selection with palivizumab in vitro or in vivo, generated similar MARM viruses with the following mutations: Lys272Met, Lys272Gln, and Asn268Ile (20,21). The Lys272Gln MARM virus completely resisted prophylactic palivizumab treatment (22).…”

Section: Resultsmentioning

confidence: 97%

Structural basis for nonneutralizing antibody competition at antigenic site II of the respiratory syncytial virus fusion protein

Mousa

Sauer

Sevy

et al. 2016

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

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Palivizumab was the first antiviral monoclonal antibody (mAb) approved for therapeutic use in humans, and remains a prophylactic treatment for infants at risk for severe disease because of respiratory syncytial virus (RSV). Palivizumab is an engineered humanized version of a murine mAb targeting antigenic site II of the RSV fusion (F) protein, a key target in vaccine development. There are limited reported naturally occurring human mAbs to site II; therefore, the structural basis for human antibody recognition of this major antigenic site is poorly understood. Here, we describe a nonneutralizing class of site II-specific mAbs that competed for binding with palivizumab to postfusion RSV F protein. We also describe two classes of site II-specific neutralizing mAbs, one of which escaped competition with nonneutralizing mAbs. An X-ray crystal structure of the neutralizing mAb 14N4 in complex with F protein showed that the binding angle at which human neutralizing mAbs interact with antigenic site II determines whether or not nonneutralizing antibodies compete with their binding. Fine-mapping studies determined that nonneutralizing mAbs that interfere with binding of neutralizing mAbs recognize site II with a pose that facilitates binding to an epitope containing F surface residues on a neighboring protomer. Neutralizing antibodies, like motavizumab and a new mAb designated 3J20 that escape interference by the inhibiting mAbs, avoid such contact by binding at an angle that is shifted away from the nonneutralizing site. Furthermore, binding to rationally and computationally designed site II helixloop-helix epitope-scaffold vaccines distinguished neutralizing from nonneutralizing site II antibodies.F protein | human respiratory syncytial virus | neutralizing antibodies R espiratory syncytial virus (RSV) is a highly contagious human pathogen, infecting the majority of infants before age 2 y, and is the leading cause of viral bronchiolitis and viral pneumonia in infants and children (1, 2). RSV remains a top priority for vaccine development, as thousands of deaths are recorded worldwide each year because of complications from infection (3). To date, there is no licensed RSV vaccine. A major focus of RSV vaccine development has been inclusion of the RSV fusion (F) protein, a class I fusion glycoprotein that is synthesized as a precursor and cleaved into two disulfide-linked fragments upon maturation into a trimer (4). Although the RSV virion contains two additional surface proteins, the highly-glycosylated attachment (G) protein and the small hydrophobic protein, the F protein is highly conserved among strains of RSV strains and is the major target of protective neutralizing antibodies.The F protein is known to adopt at least two major conformations: the metastable prefusion conformation and the postfusion conformation. Following attachment of the virion to a cell by the G protein, the F protein undergoes a dramatic structural rearrangement, resulting in fusion of the viral and cell membranes, and in cultured cells causes...

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Section: Resultsmentioning

confidence: 97%

Structural basis for nonneutralizing antibody competition at antigenic site II of the respiratory syncytial virus fusion protein

Mousa

Sauer

Sevy

et al. 2016

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

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“…Cotton rats (Sigmodon hispidus) obtained commercially (Harlan, Indianapolis, Ind.) were treated with intraperitoneal injections of cyclophosphamide (CY) at 50 mg/kg of body weight three times per week for 3 weeks prior to viral infection (24,48). CY treatment was continued until the end of study.…”

Section: Methodsmentioning

confidence: 99%

“…Viral RNA was extracted from infected ground lung tissue with Trizol reagent (Invitrogen, Carlsbad, CA), as described previously (47). The region from nucleotides 622 to 1225 in the RSV F gene was amplified as described above and cloned into pCR2.1-TOPO (Invitrogen) as previously described (48). The nucleotide sequences of the insert cDNAs were determined, and the proportion of different genotypes in each population was calculated based on the total number of clones sequenced.…”

Section: Methodsmentioning

confidence: 99%

“…Variant RSVs have been selected by growth of virus in the presence of antibody, including mutant selection by the murine antibody parent of PZ (2). We previously described the selection in both cell culture and cotton rats of RSVs resistant to PZ; all had mutations in the F protein (46)(47)(48). Fitness for replication might be an important determinant of the capacity of mutant viruses to spread (7).…”

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confidence: 99%

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In Vitro and In Vivo Fitness of Respiratory Syncytial Virus Monoclonal Antibody Escape Mutants

Zhao

Liu

Chen

et al. 2006

J Virol

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Respiratory syncytial virus (RSV) is the only infectious disease for which a monoclonal antibody (MAb) is used in humans. Palivizumab (PZ) is a humanized murine MAb to the F protein of RSV. PZ-resistant viruses appear after in vitro and in vivo growth of RSV in the presence of PZ. Fitness for replication could be a determinant of the likelihood of dissemination of resistant viruses. We assessed the fitness of two PZ-resistant viruses (F212 and MP4). F212 grew less well in cell culture than the parent A2 virus and was predicted to be less fit than A2. Equal amounts of F212 and A2 were mixed and passaged in cell culture. F212 disappeared from the viral population, indicating it was less fit than the A2 virus. The MP4 virus grew as well as A2 in culture and in cotton rats. A2/MP4 virus input ratios of 1:1, 10:1, 100:1, and 1,000:1 were compared in competitive replication. For all input ratios except 1,000:1, the MP4 virus became dominant, supplanting the A2 virus. The MP4 virus also dominated the A2 virus during growth in cotton rats. Thus, the mutant MP4 virus was more fit than A2 virus in both in vitro and in vivo competitive replication. Whether this fitness difference was due to the identified nucleotide substitutions in the F gene or to mutations elsewhere in the genome is unknown. Understanding the mechanisms by which mutant virus fitness increased or decreased could prove useful for consideration in attenuated vaccine design efforts.

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“…6 In contrast, in a study of 56 RSV-infected HSCT recipients, of whom 71% Such mutants have been produced in vitro and have been found in 5%-9% of children with RSV breakthrough episodes while receiving palivizumab prophylaxis. 25,26 Although not a significant clinical problem in immunocompetent children, resistant viruses might be more likely to develop because of prolonged shedding and higher levels of virus in immunosuppressed children. Polyclonal RSV antibody preparations such as RI-001, which has standardized concentrations of RSV antibody and meets the FDA guidance for treatment of patients with immune deficiency, could address both these issues.…”

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confidence: 99%

Compassionate use experience with high‐titer respiratory syncytical virus (RSV) immunoglobulin in RSV‐infected immunocompromised persons

Falsey

Koval

DeVincenzo

et al. 2017

Transplant Infectious Dis

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In Vivo Selection of Respiratory Syncytial Viruses Resistant to Palivizumab

Cited by 48 publications

References 34 publications

Structural basis for nonneutralizing antibody competition at antigenic site II of the respiratory syncytial virus fusion protein

Structural basis for nonneutralizing antibody competition at antigenic site II of the respiratory syncytial virus fusion protein

In Vitro and In Vivo Fitness of Respiratory Syncytial Virus Monoclonal Antibody Escape Mutants

Compassionate use experience with high‐titer respiratory syncytical virus (RSV) immunoglobulin in RSV‐infected immunocompromised persons

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