Influence of glycosylation on the immunogenicity and antigenicity of viral immunogens

Newby, Maddy L.; Allen, Joel D.; Crispin, Max

doi:10.1016/j.biotechadv.2023.108283

Cited by 6 publications

(3 citation statements)

References 283 publications

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“…Numerous reports have revealed the impact of glycan structures on the virus infectious cycle, as well as on the host immune response and the mechanism implicated in immune escape. The most known examples of extensive studies on the influence of N-glycans on the function of proteins involve influenza hemagglutinin [ 38 ], HIV env proteins [ 39 ], and, more recently, the SARS-CoV-2 S protein [ 40 , 41 ]. In many of these studies, viral glycosylation has been investigated both as a potential therapy target and in the context of vaccine design.…”

Section: Discussionmentioning

confidence: 99%

Alterations in N-glycosylation of HCV E2 Protein in Children Patients with IFN-RBV Therapy Failure

Zimmer,

Chmielewska,

Jackowiak

et al. 2024

Pathogens

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The glycosylation of viral envelope proteins plays an important role in virus biology and the immune response of the host to infection. Hepatitis C virus (HCV) envelope proteins E1 and E2, key players in virus entry and spread, are highly N-glycosylated and possess 4 (5 in certain genotypes) to 11 conserved glycosylation sites, respectively. Many published results based on recombinant proteins indicate that the glycan shield can mask the epitopes targeted by neutralizing antibodies. Glycan shifting within the conserved linear E2 region (412–423) could be one of the escape strategies used by HCV. In the present report, we isolated E2 genes from samples (collected before the IFN-RBV therapy) originating from pediatric patients infected with HCV gt 1a. We analyzed the biochemical properties of cloned E2 glycoprotein variants and investigated their glycosylation status. The sequencing of E2 genes isolated from patients who did not respond to therapy revealed mutations at N-glycosylation sites, thus leading to a lower molecular weight and a low affinity to both linear and conformational neutralizing antibodies. The loss of the glycosylation site within the conserved epitope (amino acid 417) impaired the binding with AP33, an antibody that potently neutralizes all genotypes of HCV. Our findings, based on clinical samples, confirm the influence of N-glycosylation aberrations on the antigenic and conformational properties of HCV E1/E2, which may possibly correlate with the outcome of therapy in patients.

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Section: Discussionmentioning

confidence: 99%

Alterations in N-glycosylation of HCV E2 Protein in Children Patients with IFN-RBV Therapy Failure

Zimmer,

Chmielewska,

Jackowiak

et al. 2024

Pathogens

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“…Beyond the ability to perfectly capture human-like glycan structures, glycoengineering CHO cells can also be utilized to produce therapeutic proteins having optimized glycoprofiles that impart improved binding, heightened specificity or better pharmacokinetic profiles. Modifying the native glycosylation profiles of many biologics encompassing monoclonal antibodies, protein vaccines and hormones have resulted in better therapeutic outcomes(Chen et al, 2023; Lusvarghi et al, 2023; Newby, Allen, & Crispin, 2023; Rocamora et al, 2023), and tools are emerging to enable more predictive glycoengineering of therapeutics. (Spahn, Hansen, Kol, Voldborg, & Lewis, 2017; Spahn & Lewis, 2014; Yang et al, 2015) In the case of A1AT, different diseases states of inflammation and malignancy have been shown to be associated with alternative glycoforms of the protein suggesting that variations in glycosylation could play a role in tuning the protein’s immunomodulatory properties(McCarthy et al, 2014).…”

Section: Gecho-rha1at Exhibits Both Activity and Half-life That Are I...mentioning

confidence: 99%

Glycoengineered recombinant alpha1-antitrypsin results in comparablein vitroandin vivoactivities to human plasma-derived protein

Rocamora,

Schoffelen,

Arnsdorf

et al. 2024

Preprint

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Alpha-1-antitrypsin (A1AT) is a multifunctional, clinically important, high value therapeutic glycoprotein that can be used for the treatment of many diseases such as alpha-1-antitrypsin deficiency, diabetes, graft-versus-host-disease, cystic fibrosis and various viral infections. Currently, the only FDA-approved treatment for A1AT disorders is intravenous augmentation therapy with human plasma-derived A1AT. In addition to its limited supply, this approach poses a risk of infection transmission, since it uses therapeutic A1AT harvested from donors. To address these issues, we sought to generate recombinant human A1AT (rhA1AT) that is chemically and biologically indistinguishable from its plasma-derived counterpart using glycoengineered Chinese Hamster Ovary (geCHO-L) cells. By deleting nine key genes that are part of the CHO glycosylation machinery and expressing the human ST6GAL1 and A1AT genes, we obtained stable, high producing geCHO-L lines that produced rhA1AT having an identical glycoprofile to plasma-derived A1AT (pdA1AT). Additionally, the rhA1AT demonstrated in vitro activity and in vivo half-life comparable to commercial pdA1AT. Thus, we anticipate that this platform will help produce human-like recombinant plasma proteins, thereby providing a more sustainable and reliable source of therapeutics that are cost-effective and better-controlled with regard to purity, clinical safety and quality.

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“…In addition, there seems to be little structural information available on the water network between the spike protein and its numerous glycosylations which decorate the exterior of the protein towards the solvent-exposed area [ 14 , 15 ]. As glycoproteins can obscure antibody binding epitopes and are often highly conserved, knowledge on the post-translational modifications of SARSr-CoVs may offer insight into the immunogenicity of glycoproteins and leave clues to their evolutionary history [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Variation in structural motifs within SARS-related coronavirus spike proteins

Hills,

Eruera,

Hodgkinson-Bean

et al. 2024

PLoS Pathog

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SARS-CoV-2 is the third known coronavirus (CoV) that has crossed the animal-human barrier in the last two decades. However, little structural information exists related to the close genetic species within the SARS-related coronaviruses. Here, we present three novel SARS-related CoV spike protein structures solved by single particle cryo-electron microscopy analysis derived from bat (bat SL-CoV WIV1) and civet (cCoV-SZ3, cCoV-007) hosts. We report complex glycan trees that decorate the glycoproteins and density for water molecules which facilitated modeling of the water molecule coordination networks within structurally important regions. We note structural conservation of the fatty acid binding pocket and presence of a linoleic acid molecule which are associated with stabilization of the receptor binding domains in the “down” conformation. Additionally, the N-terminal biliverdin binding pocket is occupied by a density in all the structures. Finally, we analyzed structural differences in a loop of the receptor binding motif between coronaviruses known to infect humans and the animal coronaviruses described in this study, which regulate binding to the human angiotensin converting enzyme 2 receptor. This study offers a structural framework to evaluate the close relatives of SARS-CoV-2, the ability to inform pandemic prevention, and aid in the development of pan-neutralizing treatments.

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Influence of glycosylation on the immunogenicity and antigenicity of viral immunogens

Cited by 6 publications

References 283 publications

Alterations in N-glycosylation of HCV E2 Protein in Children Patients with IFN-RBV Therapy Failure

Alterations in N-glycosylation of HCV E2 Protein in Children Patients with IFN-RBV Therapy Failure

Glycoengineered recombinant alpha1-antitrypsin results in comparablein vitroandin vivoactivities to human plasma-derived protein

Variation in structural motifs within SARS-related coronavirus spike proteins

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