Migration of the Swine Influenza Virus δ-Cluster Hemagglutinin N-Linked Glycosylation Site from N142 to N144 Results in Loss of Antibody Cross-Reactivity

Hause, Ben M.; Stine, Douglas L.; Sheng, Zizhang; Zhao, Wang; Chakravarty, Suvobrata; Simonson, Randy R.; Feng, Liang

doi:10.1128/cvi.00096-12

Cited by 12 publications

(8 citation statements)

References 30 publications

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“…The Chile/83 virus has a glycosylation site at residue 144 on its HA, along with the K147 residue (3). H1N1 swine isolates with an N-linked glycosylation site at residue 144 render these influenza viruses resistant to antibody-meditated neutralization, whereas viruses with an N142 residue instead of an N144 residue are sensitive to neutralization (19). Therefore, even if the glycan is missing on the HA immunogens and the putative neutralizing epitope is exposed to elicit high-titer antibodies to this specific epitope, if the epitope is shielded on the target HA antigen, the effectiveness of the vaccine to protect against influenza infection is decreased.…”

Section: Fig 12mentioning

confidence: 99%

N-Linked Glycans and K147 Residue on Hemagglutinin Synergize To Elicit Broadly Reactive H1N1 Influenza Virus Antibodies

Huang

Owino

Crevar

et al. 2020

J Virol

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Vaccination is the most effective way to prevent influenza virus infections. However, the diversity of antigenically distinct isolates is a challenge for vaccine development. In order to overcome the antigenic variability and improve the protective efficacy of influenza vaccines, our research group has pioneered the development of computationally optimized broadly reactive antigens (COBRA) for hemagglutinin (HA). Two candidate COBRA HA vaccines, P1 and X6, elicited antibodies with differential patterns of hemagglutination inhibition (HAI) activity against a panel of H1N1 influenza viruses. In order to better understand how these HA antigens elicit broadly reactive immune responses, epitopes in the Cb, Sa, or Sb antigenic sites of seasonal-like and pandemic-like wild-type or COBRA HA antigens were exchanged with homologous regions in the COBRA HA proteins to determine which regions and residues were responsible for the elicited antibody profile. Mice were vaccinated with virus-like particles (VLPs) expressing one of the 12 modified HA antigens (designated V1 to V12), COBRA HA antigens, or wild-type HA antigens. The elicited antisera was assessed for hemagglutination inhibition activity against a panel of historical seasonal-like and pandemic-like H1N1 influenza viruses. Primarily, the pattern of glycosylation sites and residues in the Sa antigenic region, around the receptor binding site (RBS), served as signatures for the elicitation of broadly reactive antibodies by these HA immunogens. Mice were vaccinated with VLPs expressing HA antigens that lacked a glycosylation site at residue 144 and a deleted lysine at position 147 residue were more effective at protecting against morbidity and mortality following infection with pandemic-like and seasonal-like H1N1 influenza viruses. IMPORTANCE There is a great need to develop broadly reactive or universal vaccines against influenza viruses. Advanced, next-generation hemagglutinin (HA) head-based vaccines that elicit protective antibodies against H1N1 influenza viruses have been developed. This study focused on understanding the specific amino acids around the receptor binding site (RBS) that were important in elicitation of these broadly reactive antibodies. Specific glycan sites and amino acids located at the tip of the HA molecule enhanced the elicitation of these broadly reactive antibodies. A better understanding of the HA structures around the RBS will lead to more effective HA immunogens.

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Section: Fig 12mentioning

confidence: 99%

N-Linked Glycans and K147 Residue on Hemagglutinin Synergize To Elicit Broadly Reactive H1N1 Influenza Virus Antibodies

Huang

Owino

Crevar

et al. 2020

J Virol

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“…Surprisingly, swANP32A showed mild ability to support polymerase activities of H7N9 ZJ13 and H9N2 ZJ12 (Fig 1A and 1B). Mammalian ANP32 proteins showed the support ability to the replication of mammalian influenza A viruses, including human influenza virus A/WSN/1933 (WSN) [56] (Fig 1C), swine influenza virus A/swine/North Carolina/3793/08 (H1N1 NC08 ) [57] (Fig 1D), H3N2 canine influenza virus A/canine/Guangdong/1/2011 (H3N2 GD12 ) [58] (Fig 1E), and A/equine/Xinjiang/1/2007 (H3N8 XJ07 ) [59] (Fig 1F). In addition, we noticed that some mammalian influenza viruses had lower activity in the presence of caANP32B than with caANP32A ( Fig 1).…”

Section: Avian Influenza Virus Polymerase Activity Is Stronger In Thementioning

confidence: 99%

A unique feature of swine ANP32A provides susceptibility to avian influenza virus infection in pigs

Zhang

Wang

et al. 2020

PLoS Pathog

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Both the replication and transcription of the influenza virus are catalyzed by the viral polymerase complex. The polymerases of most avian influenza A viruses have poor performance in mammalian cells, which is considered to be one of the important species barriers. Pigs have been long considered as important intermediate hosts for interspecies transmission of the avian influenza virus, because of their susceptibility to infection with both avian and mammalian influenza viruses. However, the molecular basis of influenza polymerase adaptation in pigs remains largely unknown. ANP32A and ANP32B proteins have been identified as playing fundamental roles in influenza virus replication and host range determination. In this study, we found that swine ANP32A (swANP32A), unlike swine ANP32B or other mammalian ANP32A or B, shows stronger supporting activity to avian viral polymerase. Knockout of ANP32A in pig cells PK15 dramatically reduced avian influenza polymerase activity and viral infectivity, suggesting a unique feature of swANP32A in supporting avian influenza viral polymerase. This species-specific activity is mapped to two key sites, 106V and 156S, in swANP32A. Interestingly, the amino acid 106V is unique to pigs among all the vertebrate species studied, and when combined with 156S, exhibits positive epistasis in pigs. Mutation of 106V and 156S to the signature found in ANP32As from other mammalian species weakened the interaction between swANP32A and chicken viral polymerase, and reduced polymerase activity. Understanding the molecular basis of ANP32 proteins may help to discover new antiviral targets and design avian influenza resistant genome edited pigs.

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“…RVC VP7 model has an increased surface area with highly probable antigenic properties suggesting that there might be a correlation between the degree of accessible antigenic regions and the number of N-linked glycosylation sites. Indeed, as has been suggested for HIV, glycosylation sites provide variability that allows the virus to escape immune detection of nearby conserved amino acids at the receptor-binding site and modulate antigenicity (76, 77). Further supporting this, in RV it has been possible to select monoclonal neutralization escape mutants that have new glycosylation sites in a defined epitope (78).…”

Section: Discussionmentioning

confidence: 99%

Modeling of the rotavirus group C capsid predicts a surface topology distinct from other rotavirus species

2016

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Rotavirus C (RVC) causes sporadic gastroenteritis in adults and is an established enteric pathogen of swine. Because RVC strains grow poorly in cell culture, which hinders generation of virion-derived RVC triple-layered-particle (TLP) structures, we used the known Rotavirus A (RVA) capsid structure to model the human RVC (Bristol) capsid. Comparative analysis of RVA and RVC capsid proteins showed major differences at the VP7 layer, an important target region for vaccine development due to its antigenic properties. Our model predicted the presence of a surface extended loop in RVC, which could form a major antigenic site on the capsid. We analyzed variations in the glycosylation patterns among RV capsids and identified group specific conserved sites. In addition, our results showed a smaller RVC VP4 foot, which protrudes toward the intermediate VP6 layer, in comparison to that of RVA. Finally, our results showed major structural differences at the VP8* glycan recognition sites.

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Migration of the Swine Influenza Virus δ-Cluster Hemagglutinin N-Linked Glycosylation Site from N142 to N144 Results in Loss of Antibody Cross-Reactivity

Cited by 12 publications

References 30 publications

N-Linked Glycans and K147 Residue on Hemagglutinin Synergize To Elicit Broadly Reactive H1N1 Influenza Virus Antibodies

N-Linked Glycans and K147 Residue on Hemagglutinin Synergize To Elicit Broadly Reactive H1N1 Influenza Virus Antibodies

A unique feature of swine ANP32A provides susceptibility to avian influenza virus infection in pigs

Modeling of the rotavirus group C capsid predicts a surface topology distinct from other rotavirus species

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