Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design

doi:10.1016/j.coviro.2015.02.002

Current Opinion in Virology

Volume 11, April 2015, Pages 63-69

https://doi.org/10.1016/j.coviro.2015.02.002 Get rights and content

Highlights

•
Glycosylation of enveloped viruses exhibits features of self and non-self.
•
HIV envelope displays a conserved cluster of oligomannose glycans.
•
Divergence of HIV-1 envelope glycosylation from self forms a target for bnAbs.
•
HIV-1 glycan-binding bnAbs are elicited during natural infection.

The surface of enveloped viruses can be extensively glycosylated. Unlike the glycans coating pathogens such as bacteria and fungi, glycans on viruses are added and processed by the host-cell during biosynthesis. Glycoproteins are typically subjected to α-mannosidase processing and Golgi-mediated glycosyltransferase extension to form complex-type glycans. In envelope viruses, exceptions to this default pathway are common and lead to the presence of oligomannose-type glycan structures on the virion surface. In one extreme example, HIV-1 utilises a high density of glycans to limit host antibody recognition of protein. However, the high density limits glycan processing and the resulting oligomannose structures can be recognised by broadly neutralising antibodies isolated from HIV-1 infected patients. Here we discuss how divergence from host-cell glycosylation can be targeted for vaccine design.

Introduction

The glycan structures coating the surface of bacteria, fungi, parasites and viruses are critical for disease transmission through interaction with host receptors, in particular lectins, and in shielding pathogens from the immune system. Since the discovery that conjugation of polysaccharides to carrier proteins can lead to successful T cell dependent immune responses to carbohydrates, there has been significant success in the development of polysaccharide conjugate vaccines that protect against bacterial infections including Haemophilus influenzae type b (Hib), Neisseria meningitidis and Streptococcus pneumoniae [1]. However, there are currently no carbohydrate-based vaccines that protect against viral infection. In this review we explore the scope and potential for targeting the glycan structures on viruses for vaccine design with particular reference to HIV-1 where, in some patients, glycan-binding broadly neutralising antibodies (bnAbs) are elicited during HIV-1 infection.

Section snippets

Viral glycosylation

Upon entry into a mammalian cell, a virus must replicate and produce new viral particles to sustain and spread infection. Viruses hijack the protein synthesis, glycosylation machinery and folding pathway of the host cell to produce the necessary proteins and glycoproteins required for virion production. In the endoplasmic reticulum (ER) Glc₃Man₉GlcNAc₂ is transferred to Asn residues within the glycosylation sequence Asn-X-Thr/Ser (where X can be any amino acid except Pro). Typically

Challenges for developing vaccines targeting viral glycan epitopes

Generation of antibodies to glycans has several challenges [3]. Firstly, due to the inherent weakness of carbohydrate–protein interactions binding affinities must be enhanced through avidity effects. Lectins for example are able to overcome this by using multiple carbohydrate binding domains to interact with arrays of glycan ligands. Secondly, glycoproteins usually always exist as a number of different glycoforms where the same protein backbone is glycosylated with different glycan structures [4

Envelope glycosylation exhibits features of self and non-self

Cases in which the viral glycosylation diverges from the typical pathway may present opportunities for exploiting viral glycosylation for vaccine design. The producer cell dependence of the Golgi processing phase gives rise to the capacity for viruses to exhibit antigenic shift both during inter-species and intra-species transmission and this can be pronounced in inter-species transmission of enveloped viruses. At one extreme, in the initial infection of a human host by arthropod-borne

Virion assembly and secretion pathway leave an imprint on the glycome

While cell-origin can influence the glycosylation of enveloped viruses, the viral structure and assembly pathway can also have a significant impact. A number of viruses display oligomannose-type glycans on their envelope glycoprotein and the mechanisms by which these oligomannose-type glycans are retained differ depending on the viral structure and secretion pathway. For example, unlike many enveloped viruses that bud from the infected cell membrane, HCV buds from the ER and as such the E1/E2

Dense clustering of glycans on HIV-1 leads to divergence from self

The extremely high density of glycan on the HIV-1 viral spike is unusual amongst enveloped viruses. The HIV-1 envelope glycoprotein consists of a trimer of a gp120 and gp41 heterodimer. Each gp120 subunit has a median of 25 N-linked glycosylation sites [18] and approximately 50% of its mass consists of carbohydrate making it one of the most heavily glycosylated proteins known. Although the glycans are added by the host-cell as described above, analysis of the glycans released from recombinantly

HIV-1 bnAbs target Envelope glycans

Despite the challenges described above some HIV-1 infected individuals develop antibodies capable of binding the glycans on HIV-1 Env. Approximately 10–30% of HIV-1 infected individuals develop broadly neutralising serum after 3 years of infection [29]. Over the last 5–10 years there has been a considerable effort to identify sites of vulnerability on the HIV-1 envelope glycoprotein that can be targeted for vaccine design. Several groups have isolated bnAbs from such individuals. These bnAbs

Perspective: strategies for eliciting carbohydrate-binding antibodies

There are significant challenges to overcome in the development of vaccines that target viral glycan antigens. In the case of HIV-1 the immune system has overcome these challenges and several HIV-1 infected individuals have developed glycan-binding HIV-1 bnAbs. These bnAbs typically target the non-self cluster of oligomannose-type glycans on gp120. Attempts to elicit 2G12-like bnAbs exploiting the antigenic mimicry of yeast carbohydrates [54, 55, 56] or using synthetic derived oligomannose

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

K.J.D. is supported by an MRC Career Development Fellowship (MR/K024426/1) and M.C. is supported by the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant (UM1AI100663) and the International AIDS Vaccine Initiative through the Neutralizing Antibody Consortium and Bill and Melinda Gates Center for Vaccine Discovery.

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Citation Excerpt :

Promisingly, many antibodies of exceptional neutralisation potency and breadth – bnAbs, isolated from a small percentage of infected individuals termed ‘elite neutralisers’ – directly engage glycans (Box 2). This shows that the glycan shield can be recognised by antibodies, and that such antibodies could, in principle, be raised via vaccination [10–13]. Thus, the glycan complement of Env can be viewed as both an immune evasion mechanism and a potential antibody target.

Glycans are repeating carbohydrate structures added as post-translational modifications (PTMs) to proteins, forming glycoproteins. Self-glycans found on human cells, and viral glycoproteins produced in host cells, are generally weakly immunogenic, which is necessary to avoid autoimmunity. This feature is exploited by many pathogenic viruses, which glycosylate surface proteins to evade or reduce immune recognition. The HIV type-1 (HIV-1) envelope glycoprotein (Env) is heavily glycosylated, which broadly acts to shield neutralisation-relevant protein surfaces with immunorecessive self-glycans to hinder B cell recognition. However, a small subset of HIV-1-infected individuals develops potent broadly neutralising antibodies (bnAbs), many of which directly engage the glycan shield. This provides hope that such antibodies could be elicited via vaccination and help to provide protective immunity. However, HIV-1 vaccine candidates have thus far failed to fully recapitulate such glycan-specific neutralising responses. In this review we consider the fundamental glycoimmunology and structural biology that underpin glycans in antibody evasion and as antibody targets and discuss potential approaches to harness glycan targeting for HIV-1 vaccine design.
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Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design

Highlights

Introduction

Section snippets

Viral glycosylation

Challenges for developing vaccines targeting viral glycan epitopes

Envelope glycosylation exhibits features of self and non-self

Virion assembly and secretion pathway leave an imprint on the glycome

Dense clustering of glycans on HIV-1 leads to divergence from self

HIV-1 bnAbs target Envelope glycans

Perspective: strategies for eliciting carbohydrate-binding antibodies

References and recommended reading

Acknowledgements

Blood

Cell Host Microbe

J Biol Chem

J Proteome Res

Science

Science

Nature

Science

J Virol

Nature

Science

Mol Pharm

Carbohydrate vaccines: developing sweet solutions to sticky situations?

Nat Rev Drug Discov

Assembly of asparagine-linked oligosaccharides

Annu Rev Biochem

Exploiting the defensive sugars of HIV-1 for drug and vaccine design

Nature

Glycosylation: heterogeneity and the 3D structure of proteins

Crit Rev Biochem Mol Biol

Structural plasticity of the semliki forest virus glycome upon interspecies transmission

J Proteome Res

Lectin switching during dengue virus infection

J Infect Dis

N-linked glycans on dengue viruses grown in mammalian and insect cells

J Gen Virol

Characterization of the envelope glycoproteins associated with infectious hepatitis C virus

J Virol

Uukuniemi phlebovirus assembly and secretion leave a functional imprint on the virion glycome

J Virol

Structure of the ebola virus glycoprotein bound to an antibody from a human survivor

Nature

Identification of N-glycans from ebola virus glycoproteins by matrix-assisted laser desorption/ionisation time-of-flight and negative ion electrospray tandem mass spectrometry

Rapid Commun Mass Spectrom

Crystal structure and carbohydrate analysis of nipah virus attachment glycoprotein: a template for antiviral and vaccine design

J Virol

Dimeric architecture of the hendra virus attachment glycoprotein: evidence for a conserved mode of assembly

J Virol

Unusual molecular architecture of the machupo virus attachment glycoprotein

J Virol

Evolutionary and immunological implications of contemporary HIV-1 variation

Br Med Bull

The glycan shield of HIV is predominantly oligomannose independently of production system or viral clade

PLoS ONE

Envelope glycans of immunodeficiency virions are almost entirely oligomannose antigens

Proc Natl Acad Sci U S A

Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells

J Biol Chem

Mass spectrometric characterization of the glycosylation pattern of HIV-gp120 expressed in CHO cells

Biochemistry

Mannose-rich glycosylation patterns on HIV-1 subtype C gp120 and sensitivity to the lectins, griffithsin, cyanovirin-N and scytovirin

Virology

Crystal structure of a soluble cleaved HIV-1 envelope trimer

Science

Structure and immune recognition of trimeric pre-fusion HIV-1 Env

Nature

Lack of complex N-glycans on HIV-1 envelope glycoproteins preserves protein conformation and entry function

Virology

Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning

Nat Rev Immunol