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Bitter-sweet symphony: glycan–lectin interactions in virus biology

Bitter-sweet symphony: glycan–lectin interactions in virus biology Department of Virology, Parasitology and Glycans are carbohydrate modifications typically found on proteins or lipids, Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 and can act as ligands for glycan-binding proteins called lectins. Glycans and Merelbeke, Belgium. lectins play crucial roles in the function of cells and organs, and in the Tel.: +00 32 9 264 73 75; immune system of animals and humans. Viral pathogens use glycans and lec- fax: +00 32 9 264 74 95; tins that are encoded by their own or the host genome for their replication e-mail: and spread. Recent advances in glycobiological research indicate that glycans and lectins mediate key interactions at the virus-host interface, controlling Received 29 April 2013; revised viral spread and/or activation of the immune system. This review reflects on 27 September 2013; accepted 14 October glycan–lectin interactions in the context of viral infection and antiviral 2013. Final version published online 6 December 2013. immunity. A short introduction illustrates the nature of glycans and lectins, and conveys the basic principles of their interactions. Subsequently, examples DOI: 10.1111/1574-6976.12052 are discussed highlighting specific glycan–lectin interactions and how they affect the progress of viral infections, either benefiting the host or the virus. Editor: Urs Greber Moreover, glycan and lectin variability and their potential biological conse- quences are discussed. Finally, the review outlines how recent advances in the Keywords glycan–lectin field might be transformed into promising new approaches to DC-SIGN; collectin; galectin; hemagglutinin; antiviral therapy. receptor-destroying enzyme; antiviral. this glycovirological approach has yielded a wealth of Introduction information on the various glycobiological aspects of viral Many emerging and re-emerging viral diseases in animals infection and antiviral immunity. Particularly fascinating and humans pose significant global health problems for in this context are the many distinct glycan-lectin inter- which novel antiviral measures are in urgent demand. In actions that may occur during viral infection of a host. general, rational design of new prophylactic and curative Virion-associated glycans often serve as ligands for spe- antiviral strategies requires a detailed knowledge of the cific host lectins. Conversely, the glycan portions of host viral infection mechanism and the host’s innate and glycoconjugates function as receptors for various viruses adaptive immune defense. Historically, cell biological and that employ viral lectins for host cell entry. This review microbiological research was mainly focussed on the reflects on glycan–lectin interactions in the context of nucleic acid and protein level. However, over the last few viral infection and antiviral immunity. Following a gen- decades it has become clear that also glycans account to a eral introduction on glycan and lectin biology, specific great extent for the structural and functional diversity dis- glycan–lectin interactions are highlighted and discussed played by animal and human cells and their pathogens. within the larger framework of viral infection and immu- At this moment, glycobiology is one of the most rapidly nity. Distinction is made between interactions that benefit expanding disciplines in biology. A rapidly evolving array the host and interactions that benefit the virus. In addi- of powerful, novel techniques for the analysis of glycan tion, different factors that contribute to glycan and lectin structure and function (glycomics) has prompted many variation – and that consequently affect glycan–lectin scientists to apply these tools to the field of virology, and interactions – are explored and various approaches to ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved MICROBIOLOGY REVIEWS Glycan–lectin interactions in virus biology 599 modulate specific glycan–lectin interactions in antiviral atoms of specific amino acid (aa) residues (typically therapies are briefly discussed. Asparagine) via an N-glycosidic bond. N-acetylglucos- amine–to–Asparagine (GlcNAcb-Asn) type glycans repre- sent the most common form of N-linked protein Glycans vs. lectins glycosylation (Weerapana & Imperiali, 2006; Varki et al., 2009; Larkin & Imperiali, 2011; Schwarz & Aebi, 2011; Glycans Taylor & Drickamer, 2011). O-linked glycans are cova- Like nucleic acids, proteins and lipids, glycans are essential lently attached to the oxygen atoms of specific amino components of the animal cell and organism. The term acid residues (typically Serine or Threonine) via an ‘glycan’ refers to the carbohydrate portion of glycoproteins O-glycosidic bond. A common O-glycan type – and and glycolipids typically found at cell surfaces, in extracel- potentially the one most studied – is the N-acetylgalac- lular matrices and in cell secretions. Unlike nucleic acid tosamine–to–Serine/Threonine (GalNAca-Ser/Thr) type and protein synthesis, the biosynthesis of glycans is not a or mucin-type O-glycan. Other (nonmucin) O-glycan template-driven process. Instead, glycosylation depends on types include a-linked O-mannose, a-linked O-fucose, the concerted action of different glycosyltransferase, glyco- b-linked O-xylose, b-linked O-GlcNAc (N-acetylglucos- sidase, and other enzymes. Several important glycan types amine), a-/b-linked O-galactose, and a-/b-linked O-glu- are exclusively assembled by the enzyme sets present in the cose glycans (Van den Steen et al., 1998; Peter-Katalinic, endoplasmic reticulum (ER) and the Golgi network: gly- 2005; Varki et al., 2009; Jensen et al., 2010; Gill et al., can/glycoconjugate synthesis is typically initiated in the ER 2011; Taylor & Drickamer, 2011). Interestingly, various or early Golgi and gradual processing and diversification – proteins are also modified with glycosaminoglycans or ‘maturation’ – occurs as these molecules move further (GAGs), linear polysaccharide chains composed of through the different enzyme-equipped compartments of repeated disaccharide subunits consisting of a uronic the secretory pathway. The variability inherent to glycan acid/galactose residue and an amino sugar. Glycosamino- synthesis and maturation forms the basis of the consider- glycan-carrying glycoproteins are generally referred to as able diversity and complexity of the glycan repertoires proteoglycans (Prydz & Dalen, 2000; Varki et al., 2009; found on animal glycoconjugates (Varki et al., 2009; Taylor & Drickamer, 2011). Figure 1 illustrates the gen- Taylor & Drickamer, 2011). eral structure and classification of some common types According to the basic glycan ‘core’ structure, the type of protein glycosylation. Similarly as for protein-linked of molecule the glycans are linked with and the type of glycosylation, different types of lipid-linked glycosylation the linkage, glycans and glycoconjugates can be catego- can be discerned: the glycosphingolipids (Varki et al., rized in different classes. Two major classes of protein- 2009; Taylor & Drickamer, 2011; Yu et al., 2011) and the linked glycosylation are the N- and O-linked glycans. glycophospholipid anchors or glycosylphosphatidylinosi- N-linked glycans are covalently linked to the nitrogen tol (GPI) anchors (Paulick & Bertozzi, 2008; Varki et al., Fig. 1. Classification and basic structure of common types of protein-linked glycosylation. (a) GlcNAcb-Asn type N-linked glycans are covalently attached to the amide nitrogen atoms of Asn side chains and are almost exclusively found on Asn residues within the sequence Asn-X-Ser/Thr, in which X can be any amino acid except Pro. The nature of the glycan structures that decorate the common glycan core – the glycan part shown in a dashed box – dictates classification of N-linked glycans as high-mannose type, hybrid type or complex type glycans, examples of which are shown in the panel. (b) GalNAca-Ser/Thr type O-linked glycans have a GalNAc residue a-linked to the oxygen atom of the hydroxyl group of Ser or Thr residues. Unlike for GlcNAcb-Asn type N-linked protein glycosylation, there are no clear amino acid motifs that mark these O-linked glycosylation sites. A single GalNac residue linked to the Ser/Thr is termed the ‘Tn antigen’. Depending on the basic structure of the glycan core, more complex (extended) O-linked glycans are categorized into different ‘core types’. Cores 1–4 are the most common core structures, but also other core types exist. The Tn antigen and examples of extended core 1, 2, 3, and 4 O-glycans are shown in the panel. The distinct glycan cores are shown in dashed boxes. (c) Glycosaminoglycans (GAGs) are linear polysaccharide chains composed of repeated disaccharide subunits of a uronic acid/galactose residue and an amino sugar. Glycosaminoglycans are classified as hyaluronan (HA), heparan sulfate/heparin (HS), chondroitin sulfate (CS), dermatan sulfate (DS), or keratan sulfate (KS), depending on the structure of their basic disaccharide subunits (shown in square brackets) and further modification (e.g. sulfation at different positions) of the glycan chain. With exception of hyaluronan, all major glycosaminoglycan types are sulfated and occur covalently linked to proteins. HS, CS, and DS are found on Ser-linked xylose residues. Although no unambiguous consensus sequence for xylosylation exists, the Ser attachment site is consistently flanked by a Gly residue at its carboxy- terminal side. As depicted in the figure, heparan sulfate and heparin have the same basic structure. Although they share a common biosynthesis, heparin generally undergoes more extensive sulfation and epimerization of uronic acid to iduronic acid. Moreover, heparin is synthesized only in connective tissue mast cells as part of serglycin proteoglycans, whereas heparan sulfate is synthesized in virtually all mammalian cells. KS is found on Asn-linked N-glycan core structures (KS I) or Ser/Thr-linked O-glycan core 2 structures (KS II). Capping or further modification of the glycosaminoglycan chains – sulfation excepted – is not depicted (adapted from Varki et al., 2009). FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 600 W. Van Breedam et al. (a) (b) (c) ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 601 2009; Taylor & Drickamer, 2011) represent important in-depth discussion of these is beyond the scope of this glycolipid classes. Their basic structure is introduced in review. For more detailed information on glycan struc- Fig. 2. ture and biosynthesis, readers may refer to recent refer- Despite their different core structures and linkages to ence works on this topic (Varki et al., 2009; Taylor & carrier molecules, distinct glycan types can still share con- Drickamer, 2011). served structural characteristics as they often follow par- Not only the animal and human hosts, but also their tially overlapping biosynthetic pathways. Although some pathogens can benefit from the fine-tuned cellular biosyn- glycan features may be exclusively found in one specific thetic pathways that govern glycosylation. This is most glycan class, many (sub)terminal glycan modifications can obvious in the case of obligatory intracellular pathogens be found in different glycan classes. Common (sub)termi- such as viruses. Glycans form an important part of the nal modifications include poly-N-acetyllactosamine chains, surface of many viruses. As the glycosylation of viral ABH and Lewis histo-blood group antigens (HBGA), and components is facilitated by the cellular glycosylation sialic acids in different linkages (Varki et al., 2009; Taylor machinery, viral glycosylation is similar to that of the & Drickamer, 2011). Consequently, the glycan moieties of host. However, important differences have been noted: glycoproteins and glycolipids often have more in common Viral glycoproteins are often more heavily glycosylated than one would expect based on their core structure. than their cellular counterparts and the composition of Apart from the different glycan types introduced here, individual glycan chains can diverge greatly between virus several other forms of glycosylation exist. However, an and host. The biological basis of this variability is further (a) (b) Fig. 2. Classification and basic structure of major types of lipid-linked glycosylation. (a) Glycosphingolipids consist of a hydrophilic glycan moiety linked to a hydrophobic sphingolipid. In higher animals, a ceramide lipid molecule is initially modified with a b-linked glucose or galactose residue, after which further extension and modification of the glycan moiety can occur. Extension to larger glycan chains is common on ceramide-linked glucose residues, whereas further glycan extension on ceramide-linked galactose residues is more rare. Depending on their glycan core structure, glycosphingolipids are classified in ‘series’. The figure depicts a number of glycosphingolipid core structures. The key features that characterize each series are shown in dashed boxes. Core structures can be further modified with sialic acids or sulfate groups, which allows subclassification of glycosphingolipids as neutral (lacking charged carbohydrates or ionic groups), sialylated or sulfated. (b) Glycosylphosphatidylinositol (GPI) anchors are found in association with certain membrane proteins and serve as linkers between the protein and the lipid membrane. Glycosylphosphatidylinositol anchors have a common core structure comprising ethanolamine-PO -6Mana1-2Mana1- 6Mana1-4GlcNa1-6myo-inositol-1-PO -lipid. Differential derivatization of this common core structure through lipid remodeling and modification of the glycan moiety can cause significant glycosylphosphatidylinositol anchor heterogeneity. The protein is linked to the glycosylphosphatidylinositol anchor via an amide linkage between the C-terminal carboxyl group of the protein and the amino group of phosphatidylethanolamine (adapted from Varki et al., 2009). FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 602 W. Van Breedam et al. situated later in this review (see ‘Glycan and lectin varia- ligands (avidity). Whereas some lectins contain multiple tion at the virus level’). CRDs that can participate in ligand binding, others con- In line with the similarity between viral and host tain only a single CRD and rely on clustering of individ- glycosylation, many of the basic functions covered by ual lectin molecules for high avidity binding. Clustering glycans in normal animal and human physiology and in of CRDs does not only allow stronger interactions with viral infection biology – which is intrinsically linked to ligands, but also contributes to the specificity/selectivity the biology of the host – are essentially the same. Gly- of interactions at the multivalent level. The relative spac- cans play important structural roles and are for instance ing of the CRDs allows highly avid, multivalent binding implicated in protein folding and solubility, protease to specific saccharide ligands in a certain density and par- resistance, and masking of highly immunogenic protein ticular presentation. Ultimately, the avidity of lectins for stretches (‘glycan shielding’) (Varki et al., 2009; Taylor specific glycoconjugates depends on the structure, multiv- & Drickamer, 2011). Alternatively, glycans can also have alency, and density of glycans on these molecules (Elga- nonstructural roles and take part in specific recognition vish & Shaanan, 1997; Weis, 1997; Loris, 2002; Varki events, in which they usually interact with complemen- et al., 2009; Gabius et al., 2011). tary glycan-binding proteins called lectins (Varki et al., Animal lectins are typically expressed in a cell- and/or 2009; Taylor & Drickamer, 2011). tissue-specific manner. They are involved in many differ- ent biological processes, including glycoprotein trafficking, cell adhesion and signaling, and their expression is usually Lectins tightly regulated (Varki et al., 2009). Particularly striking Lectins may simply be defined as carbohydrate-binding is the great number of membrane-associated and soluble proteins, although some definitions are more restrictive lectins that are linked with host immunity. Immune sys- and exclude mono-/oligo-saccharide transport proteins, tem lectins are involved in intercellular communication, enzymes, glycan-specific antibodies, and even glycosamino- positive and/or negative regulation of activation, regula- glycan-binding proteins (Elgavish & Shaanan, 1997; Weis, tion of inflammation, disposal of damaged and apoptotic 1997; Loris, 2002; Varki et al., 2009; Gabius et al., 2011). cells, etc. Several of these lectins have also been identified According to the more strict definitions, glycosaminogly- as ‘pattern recognition receptors’ (PRRs), which act as can-binding proteins and lectins are distinguished based molecular sensors for pathogens and endogenous stress on different factors, including their ligand range, the signals and often trigger specific immune reactions/mecha- structural basis of their glycan recognition, and their con- nisms in response to their detection (Gordon, 2002; servation (Varki et al., 2009). In general, glycosaminogly- Janeway & Medzhitov, 2002; Cambi & Figdor, 2003; McG- can-binding proteins interact with negatively charged real et al., 2004; Cambi et al., 2005; McGreal et al., 2005; glycosaminoglycans via clusters of positively charged aa Crocker et al., 2007; Crocker & Redelinghuys, 2008; van residues and – with exception of hyaluronan-binding pro- Kooyk & Rabinovich, 2008; Garcia-Vallejo & van Kooyk, teins, which seem to share an evolutionarily conserved fold 2009; Geijtenbeek & Gringhuis, 2009; Sato et al., 2009; – do not appear to be evolutionarily related to each other Bottazzi et al., 2010; Dam & Brewer, 2010; Kumagai & (Varki et al., 2009). In contrast, most strict sense lectins Akira, 2010; Svajger et al., 2010; Davicino et al., 2011; belong to protein families with defined ‘carbohydrate rec- Osorio & Reis e Sousa, 2011; Sancho & Reis e Sousa, ognition domains’ (CRD). The CRDs within a lectin family 2012). The capacity of many immune system lectins to share structural and functional properties and selectively couple glycan recognition events with specific signaling recognize specific portions of N-glycans, O-glycans, or gly- and/or effector functions gives them a key regulatory posi- colipids (sometimes also glycosaminoglycans) (Varki et al., tion in the immune system. Figure 3 gives a schematic 2009). Although some CRDs can efficiently bind monosac- overview of different types of animal lectins that are charides, other CRDs show no apparent affinity for mono- considered in this review. saccharides and favor oligosaccharide ligands. The latter Lectins play a pivotal role in different aspects of the CRD type often has a preference for ligands with specific physiology, including the immune defense against linkages between the monosaccharide subunits, as these (viral) pathogens. However, it has become apparent linkages determine the 3D structure of the glycan ligand that several viruses exploit host lectins to promote their and therefore the portions of the glycan that are available spread. In addition, many viruses encode lectins for the for interaction with the CRD. recognition of and infectious entry into target cells. Interactions between a single CRD and a single mono-/ The following section explores how glycan–lectin inter- oligo-saccharide (affinity) are often weak, and strong actions shape the virus-host interplay, mainly focussing interactions are usually the result of multivalent binding, on glycan–lectin interactions directly involving infec- i.e. the interaction of multiple CRDs with multiple tious virions. ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 603 (a) (b) FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 604 W. Van Breedam et al. Fig. 3. Schematic overview of different types of membrane-associated (a) and soluble (b) animal lectins that are considered in this review. The lectin domains are highlighted and listed in the key. C-type lectin/C-type lectin domain: Lectins are classified as C-type lectins based on their 2+ 2+ Ca -dependency and shared primary structure. In the C-type CRD, a Ca ion is directly involved in carbohydrate binding by making coordination bonds to both the CRD surface and key hydroxyl groups of the carbohydrate. The C-type lectin family contains both membrane- associated (a.1) and soluble (b.1) lectins. The collectins are soluble C-type lectins characterized by the presence of collagen-like domains. R-type lectin domain: This term refers to a CRD that is structurally similar to the CRD in ricin, a toxin found in the plant Ricinus communis. I-type lectin/ I-type lectin domain: I-type lectins are glycan-binding proteins that belong to the Ig superfamily, but are not antibodies or T-cell receptors. The ‘sialic acid-binding Ig-like lectin (siglec)’ family of membrane-associated lectins is currently the only well-characterized group of I-type lectins (a.2). Ficolin: Ficolins (b.2) are soluble lectins characterized by the presence of collagen-like domains and fibrinogen-like globular domains with a lectin activity. Galectin/S-type lectin (domain): Galectins (b.3) are soluble lectins that typically bind b-galactose-containing glycoconjugates and show primary structural homology in their CRDs. Galectins were initially referred to as S-type lectins to reflect their sulfhydryl dependency, the presence of cysteine residues and their solubility; however, at present, not all identified galectins fit this initial description anymore. Pentraxin/pentraxin domain: Pentraxins (b.4) are characterized by the presence of pentraxin domains, which contain an eight amino acid long conserved ‘pentraxin 2+ signature’ (HxCxS/TWxS, where x is any amino acid) and display an L-type (Legume-type) lectin fold. SAP is a soluble lectin that requires Ca ions for carbohydrate ligand binding (adapted from Fujita, 2002; Varki et al., 2009; Bottazzi et al., 2010). (Moris et al., 2004, 2006). Similarly, various other mem- Glycan–lectin interactions in virus brane-associated host lectins can aid as PRRs in the biology defense against viral pathogens. However, growing evi- dence illustrates that many of these lectins, including DC- Glycan–lectin interactions that benefit the SIGN, are also abused by viruses to gain access to their host target cells and facilitate viral spread, as is discussed fur- ther below. Membrane-associated host lectins can capture viruses for degradation Soluble host lectins can block viral infection and Lectins cover essential roles in the animal host’s immune target virions for destruction by the immune defense. Importantly, several membrane-associated host system (immune system) lectins act as pathogen recognition molecules: they can bind pathogens and activate signaling In contrast to the dual role played by different mem- mechanisms or capture pathogens for subsequent degra- brane-associated host lectins, soluble host lectins have dation and presentation to cells of the adaptive immune mainly been associated with protection against viral infec- system (e.g. MHCII-restricted presentation of antigens to tion. Several soluble host lectins have been reported to T cells), resulting in the induction of a pathogen-specific aid in neutralization and clearance of various viral patho- adaptive immune response. Alternatively, pathogens gens. Table 1 gives an overview of membrane-associated attached to such cell surface lectins may also be directly and soluble host lectins that are linked with the host’s presented to neighboring immune cells in trans, a process defense against different viruses. Current experimental that seems especially significant at sites with a high den- data strongly implicate these host lectins in the defense sity of immune cells (e.g. the lymph nodes). Hence, bind- against the listed viral pathogens and do not attribute ing of a viral pathogen to membrane-associated (immune explicit proviral effects to the host lectin – unlike for the system) lectins can lead to its clearance and degradation. lectin-virus pairs listed further in Table 2. The basic principles of soluble lectin-mediated antiviral A prominent example is the interaction between the protection are most easily conveyed using some specific, well- human immunodeficiency virus type 1 (HIV-1) and human langerin, a C-type lectin mainly expressed on characterized examples. For instance, various studies point Langerhans cells (de Witte et al., 2007; van der Vlist & out an important role of surfactant protein A (SP-A), surfac- Geijtenbeek, 2010). de Witte et al. (2007) reported that tant protein D (SP-D), and mannose-binding lectin (MBL) HIV-1 interacts with langerin via high-mannose glycans in the defense against influenza A virus (IAV) infection. on the gp120 envelope protein and is subsequently inter- SP-A, SP-D, and MBL are all soluble C-type lectins and nalized into Birbeck granules, leading to virus degradation share a similar basic structure: lectin monomers – consisting (de Witte et al., 2007). Also DC-SIGN, a mannose-bind- of an N-terminal cysteine-rich domain, a collagen-like ing C-type lectin mainly expressed on dendritic cells domain, a coiled coil neck domain, and a C-terminal (DCs), can bind and internalize HIV-1 virions for degra- CRD – assemble into trimers which, under physiologic dation and promotes MHCII-restricted as well as exoge- conditions, further multimerize via their N-termini to nous MHCI-restricted presentation of HIV-1 antigens form typical cruciform- (SP-D) or bouquet- (SP-A and ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 605 Table 1. Overview of host lectins that are linked with antiviral hemagglutinin with a sialylated N-glycan on the SP-A defense CRD (Hartshorn et al., 1994; Benne et al., 1995, 1997; Hartshorn et al., 1997; van Eijk et al., 2003; Mikerov et al., Host lectin Implicated in defense against … 2008). In other words: SP-D and MBL binding depend on Membrane-associated lectin dimt viral glycosylation, whereas SP-A binding mainly depends Langerin Human immunodeficiency virus , Measles virus on the specificity of the hemagglutinin, and this is mir- Soluble lectin rored in the spectrum of IAV variants these lectins can 2,3 Collectin-11 (CL-11) Influenza A virus effectively bind (Hartshorn et al., 1994; Malhotra et al., 4 4–6 Collectin-43 (CL-43) Bovine rotavirus, Influenza A virus 1994; Benne et al., 1995, 1997; Hartshorn et al., 1997; 6,7 Collectin-46 (CL-46) Influenza A virus Reading et al., 1997; Kase et al., 1999; Hartshorn et al., 4 4,6,8–12 Conglutinin Bovine rotavirus, Influenza A virus 13 2000; van Eijk et al., 2003; Mikerov et al., 2008; Hillaire Ficolin A Influenza A virus et al., 2011). Interestingly, the porcine variant of SP-D Ficolin-a Porcine reproductive and respiratory syndrome virus appears to combine the above-mentioned IAV-binding H-ficolin Influenza A virus functionalities: this molecule may not only bind IAV viri- 16,17 13 L-ficolin Hepatitis C virus, Influenza A virus ons through interaction of its CRD with high mannose 18 dimt Galectin-1 (Gal-1) Hendra virus, Nipah virus , glycans on the virion surface (similar to other SP-D mole- Parainfluenza virus type 3 cules), but also through interaction of a sialylated glycan 19,20 21 Mannose-binding Dengue virus, Hepatitis C virus, 22 on the lateral surface of its CRD with the IAV hemaggluti- lectin (MBL) Human cytomegalovirus, Human 23–29 nin (similar to SP-A) and can therefore bind to a broader immunodeficiency virus, Influenza dimt 30 array of IAV variants (van Eijk et al., 2002, 2003, 2004; A virus , Marburg virus, Severe acute 31,32 respiratory syndrome coronavirus Hillaire et al., 2011). 33–36 34 Serum amyloid P Influenza A virus, Influenza B virus, In vitro assays show that SP-A and SP-D can directly component (SAP) Parainfluenza virus type 3 neutralize IAV infectivity (Benne et al., 1995; Reading 37–39 Surfactant protein Herpes simplex virus, Human et al., 1997; Hartshorn et al., 2000; van Eijk et al., 2003; 40 dimt A (SP-A) coronavirus 229E, Influenza A virus , Hawgood et al., 2004; Hillaire et al., 2011). Both SP-A Porcine reproductive and respiratory and SP-D inhibit the viral hemagglutinating activity that syndrome virus Surfactant protein Bovine rotavirus, Human is required for IAV attachment to target cells (Hartshorn 40 dimt D (SP-D) coronavirus 229E, Influenza A virus , et al., 1994; Malhotra et al., 1994; Benne et al., 1995; 42–44 Respiratory syncytial virus, Hartshorn et al., 1996, 1997, 2000; van Eijk et al., 2002, Sendai virus 2003, 2004; Mikerov et al., 2008; Hillaire et al., 2011) and Current experimental data implicate these host lectins in the defense SP-D was reported to inhibit the viral neuraminidase against the listed viral pathogens and do not attribute explicit proviral (Reading et al., 1997; Hillaire et al., 2011). Interestingly, effects to the host lectin. both lectins also induce viral aggregation (Hartshorn References in Table 1 are listed in Supporting Information, Data S1. et al., 1994, 1996, 1997; van Eijk et al., 2003) and function dimt: discussed in main text. as potent opsonins. SP-A for instance was identified as an opsonin for IAV phagocytosis by alveolar macrophages MBL) like structures (van de Wetering et al., 2004; (Benne et al., 1997). Moreover, SP-A and SP-D were Veldhuizen et al., 2011). Despite their similar structure, shown to enhance IAV binding to neutrophils (Hartshorn these lectins show distinct glycan ligand specificities et al., 1994, 1996, 1997; van Eijk et al., 2003) and SP-D- (Veldhuizen et al., 2011) and also their interaction with IAV complexes were found to internalize upon attachment IAV and their effects on infection and spread appear to to neutrophils (Hartshorn et al., 1997; van Eijk et al., differ. Studies using distinct IAV isolates indicate that SP- 2003). Pre-incubation of IAV with SP-A or SP-D also D and MBL bind mannose-rich glycans on the viral sur- enhances the virus-induced H O responses in neutrophils 2 2 face glycoproteins hemagglutinin and neuraminidase (a (Hartshorn et al., 1994, 1996, 1997; van Eijk et al., 2003) viral lectin and a viral glycosidase, involved in IAV entry and pre-incubation of the virus with SP-D can protect and release; see discussion on viral lectins) through their neutrophils from IAV-induced deactivation (Hartshorn CRDs (Malhotra et al., 1994; Reading et al., 1997; Kase et al., 1994, 1996, 1997). MBL can counteract IAV by et al., 1999; Hartshorn et al., 2000; Hillaire et al., 2011). roughly the same mechanisms as SP-D (Hartshorn et al., Although SP-A may interact with some IAV isolates in a 1993; Anders et al., 1994; Malhotra et al., 1994; Hartshorn similar manner (Malhotra et al., 1994), binding of this et al., 1996, 1997; Reading et al., 1997; Kase et al., 1999), molecule to most of the IAV variants tested to date although its ability to activate the complement cascade appears not to involve the lectin activity of SP-A; in con- expands its capabilities (Anders et al., 1994; Reading et al., trast, virus binding depends on the interaction of the viral 1995; Chang et al., 2010). Ligand binding by MBL (or FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 606 W. Van Breedam et al. Table 2. Overview of host lectins that have been linked with proviral effects Host lectin Implicated in infection with/spread or persistence of … Membrane-associated lectin 1–3 4 5–10 2,11 12–14 Asialoglycoprotein receptor (ASGPR) Ebola virus, Hepatitis A virus, Hepatitis B virus, Marburg virus, Sendai virus 15 16,17 Blood dendritic cell antigen-2 (BDCA-2) Hepatitis C virus, Human immunodeficiency virus 15 18–20 Dendritic cell immunoreceptor (DCIR) Hepatitis C virus, Human immunodeficiency virus 21 22–34 1–3,35–41 42,43 Dendritic cell-specific intercellular Aura virus, Dengue virus, Ebola virus, Feline coronavirus, Feline immunodeficiency 44 41,45–53 54 55 adhesion molecule 3- grabbing virus, Hepatitis C virus, Herpes simplex virus, Human coronavirus NL-63, Human 56–59 60–62 nonintegrin (DC-SIGN) cytomegalovirus, Human herpes virus 8/Kaposi’s sarcoma-associated herpes virus, Human dimt 63–65 66–68 immunodeficiency virus , Human T-cell lymphotropic virus, Influenza A virus, 69 70 71 72 Junin virus, La Crosse virus, Lassa virus, Lymphocytic choriomeningitis virus, Marburg 2,41,73 74–79 80 virus, Measles virus, Porcine reproductive and respiratory syndrome virus, Punta Toro 81 82 70,81 83 virus, Respiratory syncytial virus, Rift Valley fever virus, Semliki Forest virus, Severe acute 2,41,55,84–87 70 respiratory syndrome coronavirus, Severe fever with thrombocytopenia syndrome virus, 1,40,88–99 21,100 81 81 Simian immunodeficiency virus, Sindbis virus, Toscana virus, Uukuniemi virus, 32,33,101 West Nile virus 21 28–30,32,33 1,2,35,37–41 45–52,102,103 Liver/lymph node-specific intercellular Aura virus, Dengue virus, Ebola virus, Hepatitis C virus, Human 55 104 56 adhesion molecule 3- grabbing coronavirus NL-63, Human coronavirus 229E, Human cytomegalovirus, Human 1,88,99,105–108 66 69 2,41 nonintegrin (L-SIGN; DC-SIGN-related immunodeficiency virus, Influenza A virus, Junin virus, Marburg virus, 82 83 protein; DC-SIGNR) Respiratory syncytial virus, Semliki Forest virus, Severe acute respiratory syndrome 2,41,55,86,109,110 70 coronavirus, Severe fever with thrombocytopenia syndrome virus, Simian 88,90,99 21,100 32,33 immunodeficiency virus, Sindbis virus, West Nile virus 3,41,111,112 71 72 41,112 Liver/lymph node sinusoidal endothelial Ebola virus, Lassa virus, Lymphocytic choriomeningitis virus, Marburg virus, cell C-type lectin (LSECtin) Severe acute respiratory syndrome coronavirus 113,114 115 73,113 Macrophage Gal/GalNAc-specific Ebola virus, Influenza A virus, Marburg virus C-type lectin (MGL) 34 116–123 115,124 125 Mannose receptor (MR) Dengue virus, Human immunodeficiency virus, Influenza A virus, Visna/Maedi virus 126–132 129 Paired immunoglobulin-like type 2 Herpes simplex virus, Pseudorabies virus receptor alpha (PILR-a) 133–135 136–139 Siglec-1 (Sialoadhesin) Human immunodeficiency virus, Porcine reproductive and respiratory syndrome virus 140 140 Siglec-4 (Myelin-associated Herpes simplex virus, Varicella-zoster virus glycoprotein; MAG) Soluble lectin dimt 141 Galectin-1 (Gal-1) Human immunodeficiency virus , Human T-cell lymphotropic virus 36,142–144 142,144 142,144 144–146 Mannose-binding lectin (MBL) Ebola virus, Hendra virus, Nipah virus, West Nile virus 147 148–152 Surfactant protein A (SP-A) Human immunodeficiency virus, Respiratory syncytial virus 153,154 Surfactant protein D (SP-D) Human immunodeficiency virus Although capture of a virus by these lectins may have certain antiviral effects or promote the specific immunity against this pathogen, current experimental data suggest that the listed viruses may also employ these lectins to promote viral infection, spread or persistence. References in Table 2 are listed in Supporting Information, Data S2. dimt: discussed in main text. alternatively ficolins) can lead to activation of MBL-asso- the antiviral potential of these soluble lectins in vivo ciated serine proteases (MASPs) and initiate the comple- (LeVine et al., 2001, 2002; Zhang et al., 2002; Li et al., ment cascade via the so-called lectin pathway (Blue et al., 2002; Hawgood et al., 2004; LeVine et al., 2004; Kingma 2004; Bottazzi et al., 2010). Complement deposition on a et al., 2006; Chang et al., 2010). Noteworthy caveats virus may interfere directly with crucial steps in the viral regarding these in vivo studies are, however, that direct infection process (e.g. receptor binding), but can also trig- antiviral effects of these lectins can be hard to uncouple ger complement receptor-mediated uptake of the patho- from other – e.g. immune-regulatory – effects and that gen into immune cells. In addition, for enveloped viruses, mice do not represent natural hosts for IAV. complement activation may result in membrane attack Another interesting example of antiviral activity medi- complex (MAC) formation on the viral envelope and ated by soluble host lectins was recently reported for subsequent virolysis (Blue et al., 2004; Bottazzi et al., Nipah virus (NiV): the physiologic, homodimeric form of 2010). the soluble lectin galectin-1 can inhibit NiV envelope pro- In line with the available in vitro data, recent work with tein-mediated membrane fusion (Levroney et al., 2005; SP-A-, SP-D-, and MBL-knockout mice also confirmed Garner et al., 2010). NiV encodes two viral membrane ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 607 glycoproteins – the attachment protein NiV-G and the Glycan–lectin interactions that benefit the fusion protein NiV-F – that mediate viral entry and direct virus the endothelial cell syncytia formation typically associated with NiV infection (Levroney et al., 2005; Garner et al., Viruses encode lectins as keys for viral binding 2010; Lee & Ataman, 2011). Binding of NiV-G to cell sur- and entry into target cells face receptors induces a conformational change in NiV-F, thereby activating its fusogenic activity (Levroney et al., Like their animal hosts, also viruses can benefit from 2005; Garner et al., 2010; Lee & Ataman, 2011). Galectin-1 interactions between glycans and glycan-binding proteins. associates with glycans on the NiV envelope proteins and For instance, many viruses, including HIV-1, herpes sim- interferes with the membrane fusion process in multiple plex virus–1, and Dengue virus, have been shown to ways (Levroney et al., 2005; Garner et al., 2010). Not only interact with glycosaminoglycan molecules present on tar- does galectin-1 binding directly inhibit the crucial confor- get cells (Patel et al., 1993; Chen et al., 1997; Krusat & mational change in NiV-F associated with membrane Streckert, 1997; Summerford & Samulski, 1998; Dechecchi fusion, it also reduces the lateral mobility of NiV-F and et al., 2000, 2001; Vanderheijden et al., 2001; Delputte NiV-G in the lipid membrane and consequently counter- et al., 2002; Trybala et al., 2002). Viral association with acts the physical separation of NiV-F and NiV-G that is glycosaminoglycans is usually attributed to charge-based essential for this conformation change (Garner et al., attractions between clusters of positively charged aa resi- 2010). Moreover, galectin-1 binding impedes endocytosis dues on the virion surface and the negatively charged and maturation of the NiV-F precursor NiV-F in infected glycosaminoglycan chains. The interaction with glycosa- cells (Garner et al., 2010), further illustrating the capacity minoglycans often constitutes the first contact between a of this lectin to block different stages of the viral infection/ virus and its target cell and typically increases infection replication process. efficiency. However, it has been documented for several In sum, soluble host lectins can counteract viral infec- viruses that the ability to interact with glycosaminogly- tion in various ways: they may directly neutralize virus by cans can result from adaptation to growth in cell cul- destabilizing or aggregating virions, interfere with crucial ture (Sa-Carvalho et al., 1997; Klimstra et al., 1998; steps in the viral infection process (e.g. entry), and/or Hulst et al., 2000; Mandl et al., 2001). Clearly, use of opsonize virus to facilitate uptake and degradation. Upon primary virus isolates is of crucial importance when virus binding, some soluble lectins can trigger comple- assessing the occurrence and relevance of such interac- ment deposition on the virus, which may inhibit viral tions in vivo. infection, enhance viral uptake via complement receptors Aside from potential glycosaminoglycan-binding and subsequent degradation in immune cells, and/or capacity, several viruses are endowed with a true lectin cause virolysis. activity: they carry virally encoded lectins on their sur- Considering the above, it is clear that lectins contribute face and use these as keys to gain entry into their target significantly to the host’s antiviral defense. Host lectins cells (Fig. 5a). Similar to animal lectins, such virally are involved in neutralization and clearance of free virus, encoded lectins often possess characteristic glycan bind- immune regulation, and – although not extensively dis- ing regions (‘glycan binding pockets’) and recognize cussed in this overview – the detection and clearance of specific portions of protein- and lipid-linked glycans. virus-infected cells. Figure 4 illustrates how membrane- The hemagglutinin protein of IAV is generally regarded associated and soluble host lectins can aid in antiviral as the prototype of a viral lectin. Hemagglutinin is a defense. membrane glycoprotein that forms noncovalently linked Fig. 4. Schematic overview of how membrane-associated (a) and soluble (b) host lectins are implicated in antiviral defense. (a.1) Binding of virion-associated glycans with membrane-associated host lectins can lead to virus uptake, degradation, and presentation of viral antigens to cells of the adaptive immune system. Binding may trigger specific signaling that promotes an effective antiviral immunity. (a.2) Binding of virion- associated glycans with membrane-associated host lectins may promote direct presentation of the virus to immune cells in trans. Binding may trigger specific signaling that promotes an effective antiviral immunity. (b.1) Binding of soluble host lectins to virion-associated glycans may interfere directly with viral infection by destabilizing virions, blocking interaction of the virus with its receptors or interfering with other crucial steps in the infection process (e.g. membrane fusion). Soluble host lectins may also aggregate virions, which often negatively impacts viral infectivity (not depicted). (b.2) Soluble host lectins can act as opsonins: lectin binding to virion-associated glycans may facilitate viral uptakein immune cells via lectin receptors, leading to viral degradation and potential presentation of viral antigens to cells of the adaptive immune system. Lectin binding may also trigger complement deposition on the virus (through the lectin pathway) and facilitate viral uptake via complement receptors. (b.3) Detection of virion-associated glycans by soluble host lectins may trigger complement deposition on the virus (through the lectin pathway), which may directly inhibit viral infection and/or elicit lysis of the (enveloped) virus. FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 608 W. Van Breedam et al. (a) (b) ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 609 homotrimers in the (viral) membrane and is responsible 2007; Bu et al., 2008; Choi et al., 2008; Donaldson et al., for both virus attachment and penetration (Skehel & 2008; Shirato, 2011), rabbit hemorrhagic disease viruses Wiley, 2000; Harrison, 2008; Gamblin & Skehel, 2010). (Ruvoen-Clouet et al., 2000; Rademacher et al., 2008; The mature hemagglutinin protein consists of two disul- Guillon et al., 2009; Nystrom et al., 2011), and the rhesus fide-linked subunits, termed HA1 and HA2 (Skehel & monkey Tulane virus (Farkas et al., 2010) – were found Wiley, 2000; Harrison, 2008; Gamblin & Skehel, 2010). to interact with specific HBGA types. The HA1 subunit forms the globular ‘head’ region of Although a broad spectrum of viruses has evolved to hemagglutinin that covers the lectin function of this use viral lectins to secure efficient target cell infection, the molecule: sialic acid-binding pockets in the membrane use of viral lectins for cellular attachment comes with a distal part of HA1 allow interaction with sialic acid- price. The glycan receptors for viral lectins are not neces- containing receptors on target cells (Skehel & Wiley, sarily target cell-specific and, whereas low affinity/avidity 2000; Harrison, 2008; Gamblin & Skehel, 2010). Varia- interactions may be reversible, high affinity/avidity bind- tion in the HA1 subunit determines the affinity and ing of viral lectins to nontarget cell-associated glycoconju- specificity (e.g. a2-3- vs. a2-6-linked sialic acids) of this gates (‘decoy receptors’) can prevent the virus from molecule (Skehel & Wiley, 2000; Gamblin & Skehel, efficiently targeting susceptible host cells. In line with this, 2010). As seen for animal lectins, also hemagglutinin it was shown for IAV that interaction of the viral lectin binds with its glycan counterparts with a relatively low hemagglutinin with soluble, sialylated host glycoproteins affinity and efficient virus attachment and entry depends – e.g. SP-A (cfr. supra) or a2-macroglobulin – can inter- on the interaction of multiple hemagglutinin molecules fere with the viral hemagglutinating activity that is crucial with multiple sialic acid-containing receptors (Skehel & for receptor binding (Rogers et al., 1983; Pritchett Wiley, 2000; Gamblin & Skehel, 2010). The stalk-like & Paulson, 1989; Ryan-Poirier & Kawaoka, 1991; HA2 subunit of hemagglutinin mediates the pH-depen- Matrosovich et al., 1992; Ryan-Poirier & Kawaoka, 1993; dent fusion process upon internalization of the IAV Hartshorn et al., 1994; Malhotra et al., 1994; Benne et al., virion in the endosomal compartment of the target cell 1995; Gimsa et al., 1996; Benne et al., 1997; Hartshorn (Skehel & Wiley, 2000; Harrison, 2008; Gamblin & et al., 1997; Matrosovich et al., 1998; van Eijk et al., Skehel, 2010). 2003; Mikerov et al., 2008; Chen et al., 2010; Cwach Similar to IAV, various other enveloped [e.g. influenza et al., 2012). B and C viruses (Nakada et al., 1984; Herrler et al., Although the presence of ‘high avidity’ glycan decoys 1985a; Rogers et al., 1986; Vlasak et al., 1987; Herrler invariably puts a strain on viral infection efficiency, this et al., 1988; Herrler & Klenk, 1991; Herrler et al., 1991; burden may be lighter on viruses that are equipped with a Rosenthal et al., 1998; Lamb & Krug, 2001; Suzuki & Nei, receptor destroying enzyme (RDE) that matches the speci- 2002; Wang et al., 2007b; Wang et al., 2008a), mumps ficity of the viral lectin. Intriguingly, the best-known virus (Bowden et al., 2010; Harrison et al., 2010; Chang examples in this context are again influenza viruses. As sit- & Dutch, 2012)] as well as nonenveloped [e.g. murine uated above, both influenza A and B viruses display hem- norovirus (Taube et al., 2009, 2012), feline calicivirus agglutinin proteins on their surface, which bind to sialic (Stuart & Brown, 2007), and rhesus rotavirus (Dormitzer acids displayed on the host cell surface and mediate et al., 2002), among others (Taube et al., 2010)] viruses pH-dependent fusion of the viral membrane with the host employ sialic acid-binding viral lectins to infect target cell membrane (Skehel & Wiley, 2000; Lamb & Krug, cells. Importantly however, viral lectins with a different 2001; Wang et al., 2007b; Wang et al., 2008a; Harrison, glycan specificity have also been identified. For instance, 2008; Gamblin & Skehel, 2010). An RDE activity was many viruses – including human noroviruses (Estes et al., mapped to another viral membrane glycoprotein, desig- 2006; Le Pendu et al., 2006; Cao et al., 2007; Tan & Jiang, nated neuraminidase (Gottschalk, 1957; Colman, 1994; Fig. 5. (a) illustrates how viral lectins promote target cell infection. (b) shows how many viruses that employ viral lectins also benefit from a matching receptor-destroying enzyme (RDE) activity, which provides a counterweight against (high avidity) lectin activity. (a) Interaction of viral lectins with glycosylated receptors on a target cell promotes viral entry and infection (attachment/internalization/fusion, depending on specific virus biology). (b) Although they clearly benefit the virus, the use of (high avidity) viral lectins comes with a price. For instance, viral lectin activity can cause virions to aggregate (b.1) and can impair efficient release of newly formed virions from (glycosylated) infected cells (b.2). Moreover, binding of viral lectins to nontarget cell-associated glycoconjugates (decoy receptors) can prevent the virus from efficiently targeting susceptible host cells (b.3). Intriguingly, several lectin-carrying viruses are also equipped with an RDE that matches the specificity of the viral lectin and provides a counterweight against lectin-mediated glycan binding. In fact, for viruses equipped with both viral lectins and RDEs, a functional balance between these molecules appears to be an important determinant of the viral (replicative) fitness. FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 610 W. Van Breedam et al. (a) (b) ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 611 Lamb & Krug, 2001; Gamblin & Skehel, 2010). This proteins combine a hemagglutinating activity with a sia- enzyme removes sialic acid moieties from glycoproteins late-O-acetylesterase activity (de Groot, 2006). Interest- and glycolipids by catalyzing the hydrolysis of the ingly, for some coronaviruses, the hemagglutinin-esterase a-ketosidic linkage to the subterminal sugar residue and protein is not the only envelope protein endowed with a consequently destroys potential receptors for the viral lectin activity. For example, the spike proteins of bovine hemagglutinin (Gottschalk, 1957; Colman, 1994; Lamb & coronavirus and human coronavirus OC43 have been Krug, 2001; Gamblin & Skehel, 2010). Viral use of an shown to be potent sialic acid-binding lectins (Schultze enzyme that can actually destroy receptors for the virus et al., 1991; Kunkel & Herrler, 1993). Also the spike pro- may seem peculiar at first. Importantly, however, the tein of the transmissible gastroenteritis coronavirus of neuraminidase activity can prevent virions from aggregat- pigs has been shown to possess such a lectin activity ing via hemagglutinin-sialic acid interactions, promotes (Schultze et al., 1996; Krempl et al., 1997, 2000; Schweg- efficient release of newly formed virions from (sialic acid- mann-Wessels et al., 2011). However, transmissible gas- carrying) infected cells, and provides a counterweight to troenteritis coronavirus has no hemagglutinin-esterase the interaction of hemagglutinin molecules with nontarget protein that serves as RDE to counteract the hemaggluti- cell-associated glycans: neuraminidase-mediated removal nating activity of the spike protein. of sialic acids from decoy receptors prevents virions from establishing high-avidity interactions with these glycocon- Viruses exploit membrane-associated host lectins jugates and may even provide an escape route for virions to promote infection of target cells and avoid after hemagglutinin-mediated binding to nontarget cell- immune recognition associated glycans (Colman, 1994; Suzuki et al., 1994; Gimsa et al., 1996; Barrere et al., 1997; Gamblin & Skehel, Viruses do not only benefit from virally encoded lectins, 2010). Conceivably, a functional balance between the but can also use host lectins to their advantage. Paradoxi- hemagglutinin and neuraminidase activities is an impor- cally, many of the host lectins that are exploited by tant determinant of the (replicative) fitness of IAV vari- viruses form part of the immune system. Although cap- ants in vivo. Using IAV as a paradigm, Fig. 5b illustrates ture of viral pathogens by these lectins may have certain how viral RDE activity can balance the high avidity of antiviral effects or promote the specific immunity against viral lectins where favorable and consequently improve this pathogen (cfr. supra), many viruses can also employ viral infection efficiency. such interactions to promote efficient infection and In contrast to influenza A and B viruses, other viruses spread or to facilitate persistence (Table 2). Virus binding combine both lectin and RDE functions in one protein to membrane-associated lectins can lead to concentration complex. For example, the viral membranes of mumps of virions at the cell surface and can facilitate infection of virus, Newcastle disease virus, Sendai virus, and human target cells. In many cases, host lectins appear to function parainfluenza virus 3 and 5 are studded with hemagglu- as true portals for viral entry: the virus binds to the lec- tinin-neuraminidase proteins (Bowden et al., 2010; tin, which drives subsequent internalization of the virus Harrison et al., 2010; Chang & Dutch, 2012). Another into specific cellular compartments from which the virus example is the influenza C virus, which carries the hem- can initiate the next stage of infection. However, it has agglutination, RDE and fusion protein functions in one also been shown that lectins present on non-target cells single envelope protein named the hemagglutinin- may facilitate infection of target cells, a process called esterase-fusion protein (Nakada et al., 1984; Herrler trans-infection. Many membrane-associated (immune sys- et al., 1985a, b; Rogers et al., 1986; Vlasak et al., 1987; tem) lectins also participate in specific signaling pathways Herrler et al., 1988; Schauer et al., 1988; Herrler & and engagement of such lectins by a virus may modulate Klenk, 1991; Herrler et al., 1991; Rosenthal et al., 1998; both viral infection and the immune response in favor of Pekosz & Lamb, 1999; Lamb & Krug, 2001; Suzuki & the pathogen. Nei, 2002). Whereas the RDE of influenza A and B An immune system lectin that can be used as a para- viruses is a neuraminidase, which cleaves off entire sialic digm in this context is DC-SIGN. This molecule is mainly acid residues, the RDE of influenza C functions as a expressed on dendritic cells (DCs), but expression on dis- sialate-O-acetylesterase and cleaves off specific O-acetyl tinct other cell-types – including macrophages, B lympho- groups (Herrler et al., 1985b; Vlasak et al., 1987; Herrler cytes, platelets, and (immortalized) podocytes – has also et al., 1988; Schauer et al., 1988; Pekosz & Lamb, 1999). been described (Geijtenbeek et al., 2000a, b; Soilleux A similar situation is seen for certain coronaviruses and et al., 2002; Granelli-Piperno et al., 2005; Gurney et al., toroviruses that carry an accessory protein called hemag- 2005; Chaipan et al., 2006; Rappocciolo et al., 2006; glutinin-esterase on their surface (de Groot, 2006). As Mikulak et al., 2010; Svajger et al., 2010). Prototypic DC- the name implies, functional hemagglutinin-esterase SIGN molecules consist of a C-terminal C-type CRD, a FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 612 W. Van Breedam et al. neck region made up of 7 and a half 23 aa residue which constitute optimal ligands for DC-SIGN (van Li- repeats, a transmembrane domain, and a cytoplasmic empt et al., 2006). Nevertheless, virus originating from domain containing motifs involved in receptor internali- different host cell types can display a different glycosyla- zation and signaling (Svajger et al., 2010; Tsegaye & Pohl- tion profile, and this may modulate the efficiency of DC- mann, 2010). Lectin monomers typically multimerize via SIGN recruitment (Lin et al., 2003). their neck regions to form tetramers, which in turn orga- Binding of HIV-1 to DC-SIGN can entail both nega- nize in nanoclusters on the cell membrane (Svajger et al., tive and positive effects for the virus. In DC-SIGN- 2010; Tsegaye & Pohlmann, 2010; Manzo et al., 2012). expressing antigen-presenting cells, most of the DC-SIGN functions as a receptor for various ligands. The DC-SIGN-captured virions appear to be internalized into T cell-expressed molecule ICAM-3 is probably its most the endolysosomal pathway and rapidly degraded (Moris prominent endogenous ligand: DC-SIGN binds ICAM-3 et al., 2004; Turville et al., 2004). In line with this, on the T cell surface and thereby contributes to the tran- DC-SIGN was found to promote MHCII-restricted pre- sient, nonantigen-specific interaction of DC with T cells sentation of HIV-1 antigens (Moris et al., 2006). Intrigu- that is required for efficient screening of MHCII-peptide ingly however, in cells that co-express CD4 and CCR5/ complexes and eventual T cell priming (Geijtenbeek et al., CXCR4 (HIV-1 receptor and co-receptors, respectively), 2000a; Svajger et al., 2010). Moreover, DC-SIGN has been DC-SIGN expression also facilitates HIV-1 fusion: DC- implicated in various other processes, including DC dif- SIGN efficiently captures and concentrates viral particles ferentiation, migration, and antigen capture (Svajger at the cell surface, and binding of this lectin to the HIV- et al., 2010). Over the last decade, it has become apparent 1 envelope protein appears to increase exposure of the that DC-SIGN interacts with a wide variety of viral CD4 binding site (Lee et al., 2001; Nobile et al., 2005; pathogens. Burleigh et al., 2006; Hijazi et al., 2011). Although DC- A textbook example of a virus that recruits DC-SIGN SIGN-mediated enhancement of HIV-1 fusion may pro- is HIV-1 (Lekkerkerker et al., 2006; Wu & KewalRamani, mote MHCI-restricted presentation of HIV-1 antigen 2006; Piguet & Steinman, 2007; Tsegaye & Pohlmann, (proteasome and TAP-dependent pathway) and activa- 2010; da Silva et al., 2011; van der Vlist et al., 2011). DC- tion of cytotoxic T lymphocytes (Moris et al., 2004), SIGN can bind the enveloped HIV-1 particle and mainly enhanced HIV fusion inevitably leads to more efficient recognizes mannose-rich glycans on the viral envelope infection. Indeed, several studies confirm that DC-SIGN glycoprotein gp120 (Curtis et al., 1992; Geijtenbeek et al., facilitates productive (cis-) infection in DC-SIGN- 2000a, b; Feinberg et al., 2001; Hong et al., 2002; Lin expressing cells that also co-express CD4 and CCR5/ et al., 2003; Su et al., 2004; Hong et al., 2007). The effi- CXCR4 (Lee et al., 2001; Nobile et al., 2005; Burleigh ciency of HIV-1 capture by DC-SIGN has been linked to et al., 2006; Hijazi et al., 2011). receptor density. Experiments in 293 T-Rex cells using an DC-SIGN has also been implicated in HIV-1 trans- inducible DC-SIGN expression system have shown that infection. An initial study showed that DC-SIGN can high surface expression levels of DC-SIGN correlate with efficiently capture HIV-1 particles and transfer them to optimal binding of HIV-1 particles, and that lowering the adjacent target T cells, without the need for productive DC-SIGN expression levels can significantly reduce the infection of the DC-SIGN-expressing cell (Geijtenbeek efficiency of HIV-1 binding (Pohlmann et al., 2001). et al., 2000b). Subsequent studies on the subject These data suggest that the high DC-SIGN surface expres- reported DC-SIGN-mediated internalization of infectious sion levels on certain (immature) DC subsets are compat- HIV-1 virions into low pH nonlysosomal compart- ible with optimal capture of HIV-1 virions, whereas lower ments, and advocated that the virus traffics in intracel- DC-SIGN expression levels on B lymphocytes and espe- lular compartments towards the zone of T cell contact, cially platelets may be mirrored in a less efficient HIV-1 where it is released into the infectious synapse (i.e. the capture (Baribaud et al., 2002; Boukour et al., 2006; contact zone between the virus-loaded cell and the Chaipan et al., 2006; Rappocciolo et al., 2006). Neverthe- target T cell) (Kwon et al., 2002; McDonald et al., less, studies have shown that also B lymphocytes and 2003). DC-captured HIV-1 virions as well as T-cell- platelets can effectively bind HIV-1 virions via DC-SIGN expressed CD4 and CCR5/CXCR4 were found to con- (Boukour et al., 2006; Chaipan et al., 2006; Rappocciolo centrate at the DC-T-cell interface, rendering it an ideal et al., 2006). Evidently, the interaction between HIV-1 micro-environment for efficient infection of target T and DC-SIGN is also critically dependent on the viral gly- cells (McDonald et al., 2003). Moreover, it was postu- come. Recent research has shown that virion-associated lated that DC-SIGN-mediated capture of HIV-1 virions gp120 of peripheral blood mononuclear cell (PBMC)- temporarily protects them from degradation and pre- grown virus predominantly carries oligomannose serves viral infectivity (Geijtenbeek et al., 2000b; Kwon N-glycans (Doores et al., 2010; Bonomelli et al., 2011), et al., 2002). ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 613 The above data supporting DC-SIGN-mediated cap- spread by secretion of CXCL4 (Auerbach et al., 2012; ture, uptake, intracellular transport and ultimately trans- Tsegaye et al., 2013). Clearly, further research is necessary fer of intact HIV-1 particles from DCs to target T cells to allow a better understanding of DC-SIGN-mediated were united in the ‘Trojan horse model’ of mucosal HIV-1 trans-infection and its relevance for viral infection HIV-1 transmission. This model posits that submucosal and spread in vivo. DCs capture and internalize HIV-1 virions via DC-SIGN Importantly, the role of DC-SIGN in HIV-1 infection and, by homing to the lymph nodes, provide a means of appears not to be restricted to purely physical capture of transport for the virus to a compartment rich in target virions for subsequent degradation or cis- or trans- cells. The virus-loaded DCs then interact with CD4 T infection. Recruitment of DC-SIGN by HIV-1 also trig- cells and the virions are transferred to the target T cell gers signal transduction that modulates immune via the infectious synapse, ultimately resulting in efficient responses and infection of DCs and adjacent target cells target cell infection (Geijtenbeek et al., 2000b; Baribaud more indirectly. For example, Hodges et al. (2007) et al., 2001; Sewell & Price, 2001). However, recent reported that binding of HIV-1 to DC-SIGN compro- research is not always in line with this initial model and mises DC maturation and primes these cells for has challenged several of its key features. Cavrois et al. trans-infection: Upregulation of CD86 and MHCII is sup- (2007) reported that HIV-1 trans-infection does not pressed, whereas synapse formation between DCs and require intracellular virus trafficking, but primarily CD4 T cells is promoted (Hodges et al., 2007). More- depends on cell surface-associated virions that reach the over, HIV-1 binding to DC-SIGN was shown to activate infectious synapses via transport on the cell surface Cdc42 and promote formation of membrane extensions (Cavrois et al., 2007). In line with this, Yu et al. (2008) that facilitate HIV-1 transfer to CD4 lymphocytes (Nik- reported that HIV-1 traffics towards the infectious syn- olic et al., 2011). Other work by Gringhuis et al. (2007, apse through a specialized, surface-accessible intracellular 2010) showed that binding of HIV-1 to DC-SIGN triggers compartment (Yu et al., 2008). In addition, reports stat- Raf-1 dependent signaling, which modulates toll-like ing that virus capture by DC-SIGN mainly leads to virus receptor (TLR)-elicited signals to induce synthesis of full- internalization into the endolysosomal pathway and sub- length HIV transcripts as well as production of the sequent degradation (Moris et al., 2004; Turville et al., immunosuppressive cytokine IL-10 (Gringhuis et al., 2004; Moris et al., 2006) and that DC-SIGN-mediated (2007, 2010). In general, the data discussed above suggest trans-infection can only occur within the first hours after that DC-SIGN recruitment by HIV-1 might affect viral virus attachment (Turville et al., 2004) seem to down- infection and transmission, as well as the host defense play the importance of DC-SIGN-mediated trans-infec- against this pathogen in several ways. tion for efficient HIV-1 infection and spread. These and Over the last decade, DC-SIGN has become a prototype other data counter the theory that HIV-1 capture by for lectin-mediated cis- and trans-infection and has been DCs preserves viral infectivity, and suggest that the pres- implicated in the infection process of various viruses, ence – and transfer – of infectious virus at later time including HIV, Dengue virus, Ebola virus, and IAV (see points may be ascribed to productive DC infection (Tur- Table 2). Importantly, however, DC-SIGN is not the only ville et al., 2004; Nobile et al., 2005; Burleigh et al., host lectin that is (ab)used by viruses to promote target 2006; Wang et al., 2007a). It is also noteworthy that, cell infection or avoid immune recognition and clearance. whereas initial studies identified DC-SIGN as the main Various other membrane-associated host lectins seem to factor involved in HIV-1 capture and transmission by be exploited by viruses – in ways similar to DC-SIGN – to DCs (Geijtenbeek et al., 2000b), recent studies also aid cis-infection, trans-infection and/or viral persistence. implicate other lectins in this process (Turville et al., Analysis of recent literature suggests that membrane-asso- 2002; Izquierdo-Useros et al., 2012) or even conclude ciated host lectins may constitute weak links in the host’s that DC-SIGN is not involved in DC-mediated HIV-1 defense against viral pathogens (Table 2). trans-infection (Boggiano et al., 2007). Differences in virus strains, cell types, and experimental setup might in Soluble host lectins can promote viral infection part explain these conflicting data. Intriguingly, other recent work indicates that DC-SIGN-expressing B lym- Although generally implicated in antiviral defense, soluble phocytes and platelets may effectively capture and trans- host lectins may also support viral infection (Table 2). For fer infectious HIV-1 via DC-SIGN (Boukour et al., 2006; example, galectin-1 has been proposed to promote HIV-1 Chaipan et al., 2006; Rappocciolo et al., 2006), poten- infection (Ouellet et al., 2005; Mercier et al., 2008; tially implicating these cells/cell fragments in HIV-1 dis- St-Pierre et al., 2011; Sato et al., 2012). In vitro experi- semination in infected patients, although recent work ments pointed out that galectin-1 can enhance HIV-1 suggests that platelets might negatively regulate viral infection of different cell types – including human FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 614 W. Van Breedam et al. lymphoid cell lines, PBMC, CD4 T lymphocytes, and Glycan and lectin variation at the host level monocyte-derived macrophages (Ouellet et al., 2005; Mer- cier et al., 2008) – and increase HIV-1 infection in an ex Glycan formation is a very complex and versatile biosyn- vivo lymphoid tissue model (Ouellet et al., 2005). Further thetic process. In contrast to the primary amino acid experiments showed that galectin-1 accelerates virion sequences of proteins, glycan structures are not directly binding to the target cell surface, probably by crosslinking encoded in the host genome. Instead, they are synthe- viral and cellular glycans (Ouellet et al., 2005; Mercier sized in a step-wise manner via the concerted action of et al., 2008). A more recent study confirmed these find- various host-encoded glycosyltransferase, glycosidase, and ings and showed that galectin-1 binds to clusters of other enzymes. The availability of these glycoenzymes, N-linked glycans on the viral gp120 envelope protein in a the availability of precursor molecules and the accessibil- b-galactoside-dependent manner (St-Pierre et al., 2011). ity of specific glycosylation sites govern (the efficiency Data from the same study identify the HIV-1 receptor of) glycan addition and modification and hence deter- CD4 as a ligand for galectin-1 and suggest that galectin-1 mine glycan variability. The genetic make-up of the host can cross-link gp120 and CD4 (St-Pierre et al., 2011). In evidently has a major impact on glycosylation, but also sum, it appears that the dimeric lectin galectin-1 can other host-related factors can have pronounced effects. enhance HIV-1 infection efficiency by cross-linking viral Recent research has shown that different cell types within and host cell glycans and thereby promoting firmer adhe- a host can assemble radically different glycomes (Roth, sion of the virus to the target cell surface and facilitating 1996; Haslam et al., 2008) and that factors such as the virus-receptor interactions (Ouellet et al., 2005; Mercier activation (Comelli et al., 2006; Bax et al., 2007; Haslam et al., 2008; St-Pierre et al., 2011; Sato et al., 2012). et al., 2008) or infection (Lanteri et al., 2003) status of a Some studies have also attributed proviral effects to the cell can significantly influence glycosylation processes. collectins MBL, SP-A, and SP-D. For some viruses, it was Clearly, various biological factors contribute to the high reported that – under certain conditions – viral recogni- glycan heterogeneity that is seen for many animal glyco- tion by collectins may enhance cis-or trans-infection (Hic- conjugates. kling et al., 2000; Sano et al., 2003; Gaiha et al., 2008; Although host glycan variation may influence virtually Brudner et al., 2013; Madsen et al., 2013). It is conceivable all viral infections in several ways, its potential impact is that these collectins can bind the virus and subsequently probably most evident for viruses that are equipped with associate with collectin receptors on the surface of target/ viral lectins. A notable example in this context are the transmitting cells, thereby concentrating virions at the cell noroviruses, a major cause of nonbacterial gastroenteritis surface and facilitating infection or viral transfer. Never- in humans. It is well known that the viral capsids of most theless, involvement of other mechanisms (e.g. collectin- human noroviruses display an affinity for HBGAs, struc- mediated cross-linking of virus- and host cell-displayed turally related but highly polymorphic carbohydrate glycans, cfr. the galectin-1-HIV-1 example described structures found on proteins and lipids of epithelial cells above) can currently not be excluded. Further research is in the gastrointestinal and respiratory tract, on the sur- necessary to elucidate the biology behind the potential faces of red blood cells and as free antigens in body fluids proviral effects of collectins and to estimate the occurrence such as saliva, blood, and intestinal contents (Bu et al., and relevance of these events in an in vivo context. 2008; Choi et al., 2008; Shirato, 2011). Different norovi- Figure 6 gives a schematic overview of how membrane- ruses display distinct HBGA specificities and can be cate- associated and soluble host lectins can be implicated in gorized according to the (range of) HBGA structures they interactions that benefit the virus and facilitate viral infec- preferentially bind (Huang et al., 2005; Shirato, 2011). tion and spread. Human HBGA synthesis is controlled by various enzymes, including the glycosyltransferase enzymes encoded in the ABO, FUT2, and FUT3 gene loci. The presence of variant Glycan and lectin: the variable (functional or nonfunctional) alleles at these and other parameters in a biological equation relevant gene loci is a key determinant of HBGA pheno- As glycan–lectin interactions often represent key events in type, as it controls which ABH and Lewis antigens an viral infection and/or antiviral immunity, variation in gly- individual can synthesize (Le Pendu et al., 2006; Shirato, can or lectin expression and structure – either at the host 2011). Although it is still unclear whether they function or at the virus level – may significantly shift the balance as primary receptors for noroviruses, current data between host and pathogen. A basic insight into the nat- indicate that HBGAs are important determinants of ure and origin of this variability is therefore germane to a the noroviral tissue specificity. Moreover, several proper understanding of glycan–lectin interactions in the studies have established a link between HBGA geno-/ context of viral infection biology and immunology. phenotype and individual susceptibility to (clinical) ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 615 (a) (b) Fig. 6. Schematic overview of how membrane-associated (a) and soluble (b) host lectins can be implicated in interactions that benefit the virus and facilitate viral infection and spread. (a.1) Binding of virion-associated glycans to membrane-associated host lectins can promote (cis-) infection of the lectin-expressing cell: host lectins may facilitate viral attachment, internalization, and fusion (depending on specific virus biology). Viral attachment to membrane-associated host lectins may trigger signaling mechanisms that facilitate viral infection, spread, and/or immune evasion. (a.2) Binding of virion-associated glycans to membrane-associated host lectins can promote presentation of the virus to susceptible target cells in trans, thereby facilitating target cell infection. Viral attachment to membrane-associated host lectins may trigger signaling mechanisms that facilitate viral infection, spread, and/or immune evasion. (b.1) Multivalent soluble host lectins may facilitate virus attachment and promote viral infection by crosslinking virus- and host cell-displayed glycans. (b.2) Virus recognition by soluble host lectins and subsequent association with target cell-expressed lectin receptors may promote cis-infection of target cells. In a similar manner, soluble host lectins may capture and concentrate virions on a cell surface for subsequent presentation to target cells in trans (not depicted). Moreover, lectin binding can trigger complement deposition on the virus (through the lectin pathway), which may potentially promote cis- or trans-infection via cell surface-expressed complement receptors (not depicted). FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 616 W. Van Breedam et al. infection with specific norovirus variants: HBGA pheno- ent neck domain length variants of DC-SIGN – carrying types matching the specificity of the viral lectin correlate variable numbers of 23-aa-residue repeats in the neck with a higher risk of (clinical) infection, whereas non- region – and correlated neck domain length heterozygos- matching HBGA phenotypes correlate with relative resis- ity with a reduced risk of HIV-1 infection. Recent experi- tance (Le Pendu et al., 2006; Shirato, 2011). mental data provide evidence that naturally occurring Several studies have revealed significant heterogeneity DC-SIGN neck domain variants can differ in multimer- relating to animal lectins. Lectin expression is governed ization competence in the cell membrane and display by various genetic and nongenetic (e.g. hormone balance, altered glycan binding capacity (Serrano-Gomez et al., immune status) factors. Importantly, gene polymorphisms 2008). Moreover, the presence of such neck domain vari- that affect protein expression and/or functionality have ants appears to modulate multimerization of the proto- been described for several animal lectins, including MBL typic DC-SIGN molecule (Serrano-Gomez et al., 2008). and DC-SIGN. The fact that neck domain variation may influence the For MBL, mutations in the promoter region of the presence, stability, and functionality of DC-SIGN multi- MBL2 gene were found to affect protein expression levels, mers on the cell surface can provide a molecular explana- probably by influencing binding of transcription factors tion for the link between DC-SIGN polymorphisms and (Eisen & Minchinton, 2003; Dommett et al., 2006; susceptibility to HIV-1 and other pathogens, although Heitzeneder et al., 2012). Moreover, specific polymor- further research is needed to substantiate this (Serrano- phisms in MBL2 exon 1, encoding the collagen-like Gomez et al., 2008). domain of MBL, appear to hinder correct and stable olig- omerization of MBL protein chains and impede efficient Glycan and lectin variation at the virus level ligand binding and activation of the lectin complement pathway (Eisen & Minchinton, 2003; Dommett et al., Although viruses rely on the host cell machinery for glyco- 2006; Heitzeneder et al., 2012). Several studies suggest a conjugate synthesis, viral glycosylation profiles can signifi- correlation between MBL deficiency and susceptibility to cantly differ from the standard glycosylation profile of HIV infection, but conflicting data have been reported their host cell. For instance, it is well known that viral gly- and further research is clearly necessary to corroborate coproteins are often more heavily glycosylated than host this link (Eisen & Minchinton, 2003; Dommett et al., glycoproteins, and that also the nature of their glycan 2006; Heitzeneder et al., 2012). modifications can significantly differ. A prototypic exam- Similar findings have been recorded for DC-SIGN. ple in this context is the gp120 glycoprotein of HIV-1. Polymorphisms in the promoter region of the DC-SIGN- The HIV-1 envelope is studded with trimers of noncova- encoding CD209 gene can affect protein expression levels lently associated gp120/gp41 heterodimers (White et al., and have been linked with altered susceptibility to and/or 2010). Gp120 is one of the most heavily N-glycosylated altered disease progression after infection with several proteins in nature: it contains more than 20 N-linked gly- viral pathogens, including HIV-1 and Dengue virus cosylation sites, and N-glycans account for about half of (Martin et al., 2004; Sakuntabhai et al., 2005; Koizumi its molecular weight (Zhu et al., 2000; Wei et al., 2003; et al., 2007; Selvaraj et al., 2009; Wang et al., 2011; Pantophlet & Burton, 2006; Scanlan et al., 2007). Intrigu- Boily-Larouche et al., 2012). Moreover, distinct gene ingly, whereas mammalian glycoproteins typically carry polymorphisms in the DC-SIGN-encoding region as well mainly complex type N-glycans, this is not the case for the as alternative splicing events give rise to different iso- viral gp120 glycoprotein. Recent reasearch has shown that forms of the protein, ranging from variants containing virion-associated gp120 of PBMC-grown virus – as single nucleotide polymorphisms (SNPs) to variants with opposed to recombinantly expressed monomeric gp120 – truncated lectin domains, variable numbers of 23-aa-resi- predominantly carries oligomannose N-glycans (Doores due repeats in the neck domain, alternative cytoplasmic et al., 2010; Bonomelli et al., 2011). The synthesis of this domains or a lacking transmembrane region (Mummidi unusual glycosylation profile appears to be partially direc- et al., 2001; Liu et al., 2004; Serrano-Gomez et al., 2008; ted by the structure of the gp120/gp41 spike itself: the Boily-Larouche et al., 2012). Information on the expres- presence of a dense N-glycan cluster in gp120, combined sion and biological activity of most of these DC-SIGN with the steric consequences of gp120/gp41 trimerization, variants is rather limited. Recently, however, Boily- seems to hinder further processing of (normally transient) Larouche et al. (2012) reported that naturally occurring biosynthetic glycan intermediates by ER and Golgi genetic variants of DC-SIGN, carrying specific SNPs in a-mannosidases, ultimately yielding HIV-1 virions with the neck domain-encoding exon 4, have an enhanced oligomannose-enriched gp120 glycoproteins (Zhu et al., capacity to capture and transfer HIV-1 virions to CD4 T 2000; Doores et al., 2010; Eggink et al., 2010; Bonomelli lymphocytes. Moreover, Liu et al. (2004) described differ- et al., 2011). Clearly, although viral glycosylation is ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 617 critically dependent on the glycosylation machinery of the thus creating a ‘glycan mismatch’ with DC-SIGN. Due to host cell, the genetic and structural background of a virus this mismatch, newly synthesized DC-derived virus will can have a decisive influence in this process. not readily reinfect DCs via DC-SIGN, but preferentially Importantly, viral infection itself may also have strong infect other potential host cells via other receptors (De- repercussions on the glycosylation biology of a host cell. jnirattisai et al., 2011). Although much more research is Considering the restricted glycosylation enzyme and pre- needed to verify this tentative model, it elegantly illus- cursor availabilities, it is conceivable that overexpression trates how cell type-dependent glycan variability may of viral glycoproteins in an infected target cell can result impact a viral infection process. in an increased glycan heterogeneity of both viral and cel- Another notable factor to be considered in the context of lular glycoconjugates. Moreover, viruses may also actively virus-related variability is the rapid evolution of many viral modify the host and viral glycome by modulating the pathogens. This seems especially significant for RNA expression of host cell glycoenzymes (Hiraiwa et al., 1997; viruses, as these viruses generally evolve more rapidly than Cebulla et al., 2000; Hiraiwa et al., 2003) or via expres- DNA viruses due to factors inherent to their biology and sion of virally encoded glycoenzymes in infected cells infection strategy (Belshaw et al., 2008; Holmes, 2009; (Jackson et al., 1999; Willer et al., 1999; Nash et al., 2000; Lauring & Andino, 2010). The higher mutation frequency Sujino et al., 2000; Vanderplasschen et al., 2000; of many RNA viruses directly implies a higher chance for Markine-Goriaynoff et al., 2003, 2004a, b). addition or deletion of putative glycosylation sites. As has An additional source of glycan variation can be dis- been shown for IAV, acquisition or deletion of glycosyla- cerned for viruses that can infect multiple cell types, or tion sites may affect crucial steps in the viral infection/rep- even different host species. For instance, it is well known lication process (e.g. receptor binding, fusion, release of that HIV can productively infect multiple cell types, and newly formed virions) (Ohuchi et al., 1997; Wagner et al., that HIV glycosylation is cell type-dependent (Liedtke 2000; Tsuchiya et al., 2002; Kim & Park, 2012), alter the et al., 1994; Willey et al., 1996; Liedtke et al., 1997; Lin capacity of the virus to avoid induction of/recognition by et al., 2003). Cell type-dependent glycosylation differences virus-specific antibodies (glycan shielding) (Wang et al., for HIV have been shown to impact viral interaction 2009; Wei et al., 2010; Wanzeck et al., 2011; Kim & Park, with and trans-infection via DC-SIGN (Lin et al., 2003), 2012; Job et al., 2013; Sun et al., 2013), and modulate viral as well as viral sensitivity to antibody neutralization interaction with various immune system lectins (Reading (Willey et al., 1996). Another, particularly fascinating et al., 2007; Vigerust et al., 2007; Reading et al., 2009; Tate example in this context is Dengue virus (DV). DV is a et al., 2011a, b). Clearly, mutational changes in the viral mosquito-borne flavivirus that can replicate in mosquitos glycome may affect the virus-host interactome in various as well as in humans (Navarro-Sanchez et al., 2003; De- ways. Ultimately, the net benefit of a specific glycome jnirattisai et al., 2011). In humans, immature skin DCs change will determine if a glycosylation variant may are considered the primary target cell for the virus after become dominant in the virus population. a mosquito bite, and DC-SIGN is believed to be the However, not only the viral glycosylation status, but main DV receptor on these cells (Navarro-Sanchez et al., also the affinity and specificity of viral lectins for specific 2003; Dejnirattisai et al., 2011). In a recent study, it was glycoconjugates may change as a result of mutations. For shown that insect cell-derived DV can efficiently infect instance, ample data show that amino acid changes at DCs, whereas DC-derived DV is not able to reinfect DCs specific sites of the IAV hemagglutinin protein can signif- (Dejnirattisai et al., 2011). Similarly, insect cell-derived icantly alter its affinity and/or specificity for particular DV could efficiently bind and infect a DC-SIGN-expes- sialic acid-containing receptors – a factor that is crucial sing cell line, whereas this was not the case for DC- for the virus to infect new host species (Skehel & Wiley, derived DV (Dejnirattisai et al., 2011). Finally, it was 2000; Wagner et al., 2002; Suzuki, 2005; Gamblin & Ske- found that insect cell-derived DV predominantly contains hel, 2010). Finally, functional alterations in the viral RDE high-/pauci-mannose-type N-glycans, whereas DC- due to mutations may also have a strong impact on the derived virus contains only complex type N-glycans interaction of viral lectins with host cell glycans. In the (Dejnirattisai et al., 2011). Projected against the back- case of IAV, balanced lectin and RDE functions appear to ground of DV infection, these data outline a tentative be crucial for efficient viral replication. For IAV variants model of the first stages of DV infection in humans: dur- that are well adapted to a certain host species, the sub- ing DV replication in mosquito cells, newly formed DV strate specificity and activity of the neuraminidase gener- virions obtain mannose-rich glycans. Upon viral transfer ally match the ligand specificity and affinity of the to a human host, these virions efficiently infect immature hemagglutinin (Wagner et al., 2002). Disruption of this skin DCs via DC-SIGN. Importantly, DV replication in balance – for instance due to reassortment or transmis- skin DCs yields virions with complex type N-glycans, sion to a new host species – often results in a decreased FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 618 W. Van Breedam et al. replicative fitness (Wagner et al., 2002). Interestingly, can compromise binding of HIV-1 gp120 with DC-SIGN however, the virus may overcome this hurdle and evolve (Wang et al., 2008b; Luallen et al., 2009; Martinez-Avila towards replicative competence by selecting for compen- et al., 2009b; Becer et al., 2010) and inhibit DC- satory mutations in hemagglutinin and/or neuraminidase SIGN-mediated trans-infection of CD4 T lymphocytes that restore the functional balance between these mole- (Martinez-Avila et al., 2009a; Sattin et al., 2010; Berzi cules (Wagner et al., 2002). Considering these data on et al., 2012). Likewise, sialic acid-containing glycan decoys IAV, it is conceivable that the balance between viral lectin and sialic acid analogs are being evaluated for their capac- and RDE is also an important determinant of the replica- ity to block the sialic acid binding site of IAV hemaggluti- tive fitness of several other viruses. nin to inhibit interaction of the virus with sialic On a related note, glycan–lectin interactions in virus acid-containing receptor molecules on the surface of target biology are typically studied using a limited number of cells (Landers et al., 2002; Matrosovich & Klenk, 2003; (prototypic) virus variants. Although the information Matsubara et al., 2010; Papp et al., 2010, 2011). obtained in these studies can often be extrapolated to Alternatively, binding of CBAs to glycans displayed on include other virus variants, there are important excep- the virion surface can inhibit viral cis- or trans-infection tions. For IAV, for instance, it is well documented that via host cell lectins. This is elegantly exemplified in different virus variants can carry hemagglutinin lectins several recent studies, showing that mannose- as well as with distinct glycan ligand specificities and therefore asso- N-acetylglucosamine-specific CBAs can effectively prevent ciate with distinct spectra of (decoy) receptors. Moreover, DC-SIGN-mediated HIV-1 capture and subsequent trans- IAV variants can display different glycan arrays on their mission to T lymphocytes (Balzarini et al., 2010; Balzarini surface, which has been shown to modulate viral infec- et al., 2007a; Bertaux et al., 2007; Huskens et al., 2010; tion, glycan shielding, and recognition by various Hoorelbeke et al., 2011; Alexandre et al., 2012). Although immune system lectins (cfr. supra). The fact that the spe- CBA binding to host cell-associated glycans may inhibit cific genetic make-up of a virus determines specificity/ viruses that employ viral lectins, the potential of this affinity of viral lectins, co-directs viral glycosylation, etc., strategy for antiviral therapy remains virtually unexplored. and that this can be mirrored in a distinct virus-host It is noteworthy that the antiviral activity of CBAs or gly- interactome remains an important issue in glycovirology. can decoys that bind to virion surfaces is not necessarily In sum, an intricate web of glycan–lectin interactions limited to direct inhibition of crucial glycan–lectin inter- can modulate viral infection, and host and virus inherent actions, as they can mask greater portions of the virus variability in glycans and lectins adds a further layer of and interfere with other crucial (including non-glycan- complexity to this matter. lectin) interactions or steps in the infection process. Moreover, recent research on HIV-1 highlights the antivi- ral potential of CBAs from yet another angle. Although Targeting glycan-lectin interactions in the heavily glycosylated HIV-1 gp120 protein generally antiviral strategies provides multiple ligands for mannose- and GlcNAc-spe- Considering the pivotal roles of glycan–lectin interactions cific CBAs, prolonged CBA pressure selects for HIV-1 in many viral infections, interfering with these interac- variants with multiple N-glycosylation site deletions in tions seems an attractive strategy in the combat against the gp120 protein that are less sensitive to CBA-mediated these pathogens. Conversely, strategies that promote rec- neutralization (Balzarini et al., 2004, 2005a, b; Witvrouw ognition of viruses by specific immune system lectins – et al., 2005; Balzarini et al., 2006; Balzarini, 2007b, c; Bal- involved in viral inhibition and clearance – may also zarini et al., 2007b; Huskens et al., 2007). Interestingly, prove useful in antiviral therapies. Several possibilities however, deletion of N-glycosylation sites can also have been and are currently being explored. increase the immunogenicity of the virus and weaken the Perhaps the most obvious strategy to modulate glycan– glycan shield that protects the virus from recognition by lectin binding is the use of molecules that can physically virus-specific antibodies and other (nonlectin) immune interfere with these interactions. Glycan decoys (e.g. car- receptors (Botarelli et al., 1991; Back et al., 1994; Reitter bohydrate-containing drugs, sugar analogs/glycomimetics) et al., 1998; Bolmstedt et al., 2001; Kang et al., 2005), or carbohydrate-binding agents (CBAs) may be used in and may decrease the efficiency of HIV-1 trans-infection antiviral therapies to directly block key glycan–lectin inter- via immune system lectins like DC-SIGN (Hong et al., actions at the side of the lectin and at the side of the gly- 2007; Liao et al., 2011). In addition, it appears that accu- can, respectively. Binding of glycan decoys with a specific mulation of mutations under CBA pressure is often paral- lectin can inhibit binding of other ligands by this lectin. leled by a significant reduction of the viral fitness, which For instance, it has been shown that multivalent mannose- is obviously advantageous in the context of an antiviral containing molecules or mannose-based glycomimetics treatment (Balzarini et al., 2005a; Balzarini, 2007b, c). ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 619 For further information on CBAs and their potential in HIV-1-infected cells was also shown to potentiate the antiviral therapy, readers may refer to recent expert antiviral effects of mannose-specific plant CBAs towards reviews on this topic (Balzarini, 2007c; Francois & the newly produced HIV-1 virions (Balzarini, 2007a). Balzarini, 2012). These and other examples illustrate the potential of these Although the use of glycan decoys and CBAs may seem molecules as antiviral drugs. the most intuitive strategy to interfere directly with gly- Considering the various structural and nonstructural can–lectin interaction, other options exist as well. For roles of glycans, it is clear that glycome modulation can instance, similar to glycan decoys and CBAs, lectin- or also have effects beyond the alteration of glycan–lectin glycoconjugate-specific immunoglobulins may be used to binding events. For instance, interfering with host cell block specific interactions. Evidently, the increasing avail- glycosylation processes using specific inhibitors may inhi- ability of such ‘direct’ modulators of glycan–lectin inter- bit assembly of infectious virions (Leavitt et al., 1977; action is mirrored in an increasing number of potential Katz et al., 1980; Pizer et al., 1980; Herrler & Compans, antiviral applications. 1983; Montefiori et al., 1988; Pal et al., 1989; Mehta Apart from direct modulation, also strategies that et al., 1998; Dwek et al., 2002; Wu et al., 2002; Durantel influence glycan–lectin interactions more indirectly can et al., 2007; Lazar et al., 2007; Scanlan et al., 2007; be employed. In fact, many of the molecules used to Durantel, 2009; Merry & Astrautsova, 2010). Moreover, examine glycan–lectin interactions in vitro suggest them- glycome modulation may significantly alter the capacity of selves as potential therapeutics. the virus to evade recognition by virus-specific antibodies One approach to indirectly govern glycan–lectin inter- and B- and T-cell receptors via glycan shielding (Botarelli action is via the use of drugs that alter the host and/or et al., 1991; Back et al., 1994; Willey et al., 1996; Reitter viral glycome. Glycosidases and other enzymes may be et al., 1998; Bolmstedt et al., 2001; Kang et al., 2005; used to alter the glycan portions of fully formed and Aguilar et al., 2006; Wang et al., 2009; Francica et al., matured glycoconjugates. Alternatively, various drugs 2010; Kobayashi & Suzuki, 2012). Clearly, glycome-modi- may be employed to directly modify glycan synthesis: fying drugs can counteract viruses in various ways and glycoconjugates produced in the presence of such mole- constitute versatile tools in the control of viral infection. cules will obtain aberrant glycosylation, which may pro- Also other strategies that can indirectly influence gly- mote or annihilate their interaction with specific lectins. can–lectin interactions are certainly worth exploring. For Promising results in glycovirological research have high- instance, drugs that alter host or viral lectin expression lighted the antiviral potential of such compounds. For (e.g. cytokines or RNAi) may prove useful in antiviral instance, ample data indicate that sialidases may be used strategies (Ochiel et al., 2010; Relloso et al., 2002; Ge to counteract infections where sialic acids play important et al., 2003; Arrighi et al., 2004; Ge et al., 2004; Nair roles as cellular receptors for viral lectins [e.g. IAV binds et al., 2005; Yagi et al., 2010; Raza et al., 2011). Further- to sialic acid receptors on the airway epithelium (Skehel more, patients infected with a virus that employs both & Wiley, 2000; Malakhov et al., 2006; Belser et al., 2007; viral lectins and RDEs may also benefit from treatment Harrison, 2008; Chan et al., 2009; Triana-Baltzer et al., with RDE-specific inhibitors, as these can alter the bal- 2009a, b, 2010, 2011)] or as viral ligands for host lectins ance between viral lectin and RDE activity which is often that serve as portals for viral entry [e.g. sialic acids on crucial for efficient viral replication and spread. Notable the porcine reproductive and respiratory syndrome virus examples in this context are the several neuraminidase bind the macrophage-specific entry mediator sialoadhesin inhibitors that have been used successfully for the treat- (Delputte & Nauwynck, 2004; Delputte et al., 2007; Van ment of IAV infections (Kim et al., 1999; Lew et al., Breedam et al., 2010a, b)]. Sialidase treatment may also 2000; Roberts, 2001; Garman & Laver, 2004; Alymova enhance recognition of viral glycoconjugates by man- et al., 2005; von itzstein, 2007; von itzstein & Thomson, nose-specific immune system lectins that can limit viral 2009; Gamblin & Skehel, 2010; Ikematsu & Kawai, 2011). infection: in vitro experiments have shown that enzy- In sum, drugs that modulate glycan–lectin interactions – matic removal of sialic acids from the HIV-1 virion sur- either directly or indirectly – can be powerful instruments face can significantly enhance virus binding and in the combat against viral pathogens. However, the antivi- neutralization by MBL (Hart et al., 2002, 2003). In line ral strategies suggested above can also have drawbacks. with this, production of HIV-1 in the presence of the Intensive use of antiviral therapeutics may elicit rapid Golgi a1-2-mannosidase I inhibitor 1-deoxymannojirimy- selection of drug-resistant virus variants. Another possible cin – which blocks the biosynthesis of complex-type, drawback relates to the potential off-target effects of these sialylated oligosaccharides – increased susceptibility of therapies: therapeutics aimed at influencing specific the virus to MBL-mediated neutralization (Hart et al., glycan–lectin interactions that play key roles in viral infec- 2003). Interestingly, 1-deoxymannojirimycin treatment of tion processes may also affect general host glycosylation, FEMS Microbiol Rev 38 (2014) 598–632 ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved 620 W. Van Breedam et al. lectin expression or glycan–lectin interactions that are cru- in virus biology, and that future research may alter our cial for normal functioning of the host and its immune understanding and interpretation of specific interactions. defense. It is also conceivable that such drugs, despite The fact that (aspects of) viral glycobiology may change their antiviral effects, may benefit the virus in some ways. during virus-host co-evolution even advocates periodic For instance, although a glycome-modifying drug may re-evaluation of specific glycan–lectin interactions. promote viral recognition by specific immune system lec- The biology of glycans and lectins is complex and has tins that aid in viral clearance, it may also promote viral long been poorly accessible to virologists and other scien- interaction with host lectins that can aid in cis-or trans- tists outside this field. This situation is changing with the infection. Ultimately, the potential of specific agents as emergence of international glycomics consortia (e.g. Con- antiviral drugs depends on their net (antiviral) effects sortium for Functional Glycomics), which can provide in vivo. Other potential disadvantages concern the phar- state-of-the-art techniques and expertise to analyze and macokinetic properties of specific drugs. For instance, if interpret virologically/immunologically relevant glycan– glycan decoys or CBAs used in antiviral therapy show a lectin interactions. Still, there are specific pitfalls associ- broad reactivity and can respectively bind with multiple ated with glycovirological research. In vitro experiments (nontarget) lectins or glycans in the host, it is possible need to be designed and interpreted considering key that much of the antiviral effect is lost. Also, when using issues like glycan and lectin variability, the cell-type peptidic CBAs that are not native to the host, an antibody dependency of host and virus glycosylation and the influ- response might be mounted against these components, ence of the lectin-expressing cell type on the final out- leading to neutralization and/or faster clearance of the come of a glycan–lectin interaction. In addition, the active compound. In spite of these and other potential results of in vitro experiments must ultimately be com- pitfalls, it is clear that glycan decoys and CBAs, as well as pared with – and re-interpreted in the context of – data various indirect approaches to modulate glycan–lectin obtained in animal models. In fact, our current under- interaction, show potential for the treatment of diverse standing of specific glycan–lectin interactions in viral viral infections, either or not in combination with other infection is mostly based on in vitro experiments, under- antiviral strategies. A good understanding of relevant gly- lining the need for experimental validation of these can–lectin interactions facilitates specific targeting of these results in the context of the infected host. binding events and can help to minimize possible off-tar- In the context of viral infections, many different (lec- get effects and to reduce the risk of drug resistance. tin-dependent or -independent) interactions and processes take place simultaneously, resulting in a complex network of virus–host factor interaction, signaling, and effector Concluding remarks mechanisms, the net effect of which may benefit the host Glycans and lectins cover crucial roles in virus biology and or the virus. Many of the interactions taking place are not their interplay often shapes the virus-host interaction. In yet well defined and probably more are still unknown. general, the nature of the glycan, the lectin, and the spe- Key to combating viral disease is to make these black cific conditions under which their interaction occurs boxes more transparent. Synergisms between different determines the outcome of a specific binding event and branches of life sciences are essential to sustain and directs the virus to a certain fate. Based on current knowl- advance our knowledge in this important field of research. edge, it is clear that viral lectins generally facilitate viral infection and spread. On the other hand, although it may Acknowledgements seem intuitive that host lectin PRRs and other immune system lectins exclusively act in defense of the host, there The authors thank Leslie Bosseler for critical reading of is ample evidence that contradicts this. Although many the manuscript and assistance in creating the figures. host lectins are involved in the induction of an efficacious They also thank Dr Barbara Bottazzi, Dr Alberto immune response against viral pathogens, many viruses Mantovani, and Dr Antonio Inforzato (Istituto Clinico can also abuse these lectins to promote infection and Humanitas, Italy) for their advice on pentraxin biology. spread. Intriguingly, analysis of the many studies regarding W.V.B. was supported by the Flemish Institute for the the role of host lectins in viral infections suggests that sol- Promotion of Innovation by Science and Technology uble host lectins tend to be associated with antiviral activ- (I.W.T.-Flanders; SB 61491 & 63491) and the Special ity, whereas membrane-associated host lectins seem to play Research Fund of Ghent University. S.P. was supported a more dubious role and are often implicated in pro- as by the Leibniz Gemeinschaft. H.W.F. was supported by well as antiviral mechanisms (Tables 1 & 2). It is however F.W.O.-Vlaanderen and the Special Research Fund of noteworthy that the information provided in this manu- Ghent University. The authors apologize to all colleagues script reflects current views on glycan–lectin interactions whose work has not been cited due to space limitations. ª 2013 Federation of European Microbiological Societies. FEMS Microbiol Rev 38 (2014) 598–632 Published by John Wiley & Sons Ltd. All rights reserved Glycan–lectin interactions in virus biology 621 Balzarini J, Van Laethem K, Peumans WJ, Van Damme EJ, References Bolmstedt A, Gago F & Schols D (2006) Mutational Aguilar HC, Matreyek KA, Filone CM et al. (2006) N-glycans pathways, resistance profile, and side effects of cyanovirin on Nipah virus fusion protein protect against neutralization relative to human immunodeficiency virus type 1 strains but reduce membrane fusion and viral entry. 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Bitter-sweet symphony: glycan–lectin interactions in virus biology

FEMS Microbiology Reviews , Volume 38 (4) – Jul 1, 2014

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