Parvoviruses are among the smallest and superficially simplest animal viruses, infecting a broad range of hosts, including humans, and causing some deadly infections. In 1990, the first atomic structure of the canine parvovirus (CPV) capsid revealed a 26-nm-diameter T=1 particle made up of two or three versions of a single protein, and packaging about 5,100 nucleotides of single-stranded DNA. Our structural and functional understanding of parvovirus capsids and their ligands has increased as imaging and molecular techniques have advanced, and capsid structures for most groups within the Parvoviridae family have now been determined. Despite those advances, significant questions remain unanswered about the functioning of those viral capsids and their roles in release, transmission, or cellular infection. In addition, the interactions of capsids with host receptors, antibodies, or other biological components are also still incompletely understood. The parvovirus capsid’s apparent simplicity likely conceals important functions carried out by small, transient, or asymmetric structures. Here, we highlight some remaining open questions that may need to be answered to provide a more thorough understanding of how these viruses carry out their various functions. The many different members of the family Parvoviridae share a capsid architecture, and while many functions are likely similar, others may differ in detail. Many of those parvoviruses have not been experimentally examined in detail (or at all in some cases), so we, therefore, focus this minireview on the widely studied protoparvoviruses, as well as the most thoroughly investigated examples of adeno-associated viruses.
KEYWORDS: parvovirus, adeno-associated virus, canine parvovirus, capsid, antibodies, structure, ssDNA, viral receptor
GENERAL ASPECTS OF PARVOVIRUSES
Parvoviruses are among the smallest viruses, infecting a wide range of vertebrate and invertebrate animals. The viral capsid is around 26 nm in diameter and contains a linear single-stranded DNA (ssDNA) genome of about 5,000 bases. For most parvoviruses, the genome is roughly divided into two main open reading frames (ORFs) that encode the nonstructural (NS) and the structural proteins (viral proteins [VP]). Alternative splicing, internal translation initiation, and proteolysis may all produce smaller variants of these larger proteins. Most parvoviruses also have a variety of smaller genes or sequences in alternative open reading frames, such as the small alternatively translated protein (SAT) in pig and canine parvoviruses (PPV and CPV, respectively) and minute virus of mice (MVM), the membrane-associated accessory protein (MAAP), and the assembly-activating protein (AAP) in adeno-associated viruses (AAVs) (1,–3). The parvoviral capsid and virally encoded proteins have highly sophisticated interactions with their hosts and environments, and while some of those connections have recognized roles, others remain unknown. Clarifying those relationships and their roles is likely critical for better understanding the complexities behind parvoviruses’ capacity to infect a wide range of hosts, move from one host to another, and efficiently sustain transmission and viral replication.
Virus replication and pathogenicity are linked to the largest nonstructural protein, nonstructural protein 1 (NS1) (4,–7). The N terminus of NS1 has been reported to interact with the cellular binding protein coatomer subunit epsilon (COP) to control parvovirus replication by inhibiting type 1 interferon production (8). The NS1 protein may also trigger apoptosis in response to infection by activating the p38 mitogen-activated protein kinase (MAPK) and the p53-mediated mitochondrial apoptotic pathway, as well as by increasing the formation of reactive oxygen species (9). Recent research has revealed that the NS2 protein interacts with chromatin-regulating cellular proteins involved in DNA remodeling and damage response during parvovirus replication (10).
Parvoviruses have been circulating in nature for at least 90 million years based on the analysis of endogenized parvovirus sequences (11,–14), indicating that they have a very high level of host adaptation that has allowed them to sustain transmission over long periods and to adapt to a diverse variety of hosts and conditions. Furthermore, deep sequencing and other unbiased tests demonstrate that most animal species are infected with at least one parvovirus and often more (15,–18). Many of those viruses appear to produce little or no illness, while others, such as canine parvovirus (CPV) or the human B19 parvovirus, can cause fatal disease in vulnerable hosts (19, 20). Despite the broad distribution of parvoviruses in nature and their ability to infect animals of many kinds, only a few have been isolated in cell cultures or examined in detail beyond the properties predicted from the sequences. However, the basic architecture of all parvovirus capsids is similar, implying that the capsid is extremely efficient at performing the various fundamental processes—including receptor recognition, cellular trafficking, capsid disassembly, genome release, genome replication and packaging, progeny assembly, and egress. Moreover, variations in the capsids have been associated with host switching, altered transmission, or immune evasion.
Brief overview of parvoviral capsid structures.
The first parvovirus structure, of wild-type canine parvovirus (CPV), a member of Protoparvovirus, was determined in 1991, with the refined atomic coordinates being deposited in 1993 (21,–23). Since then, more than 100 capsid structures for protoparvoviruses and members of three additional (of the eight) Parvovirinae genera have been reported, as well as studies of the capsid interactions with receptors or antibody domains. Capsid structures reported include both wild-type and variant structures. Initial studies used X-ray crystallography to determine the structures of the capsids, but in recent years, cryo-electron microscopy (cryo-EM) and three-dimensional image reconstruction have been widely used to obtain atomic-resolution structures of capsids, and of capsids complexed with other ligands, in some cases without imposing the icosahedral symmetry for averaging (21, 23,–35).
The viral protein (VP) sequences of different parvoviruses may be widely diverse, but the structural topologies of their capsids are substantially conserved (36). In addition, changes in viral sequences or proteins may introduce symmetrical and asymmetrical changes in the capsid structures, creating diverse capsid surface morphologies within the overall common structures, and those may control host-specific receptor attachment, altered tissue tropisms, and antigenic diversification (26, 36,–41). In the autonomous parvoviruses, the parvoviral capsids typically contain 50 to 55 copies of the smaller capsid protein, virus protein 2 (VP2), and 5 to 10 copies of the larger capsid protein, VP1, which has an additional 20- to 30-kDa (depending on the virus) N-terminal peptide sequence (39, 41). In contrast, AAV capsids follow a different assembly stoichiometry, as those contain around 55 copies of the small virus protein 3 (VP3) and around 5 copies of each of the larger capsid proteins, VP1 and VP2 (42,–45). The capsid protein products from the members of the Protoparvovirus genus are produced by alternative splicing of a single mRNA transcript encoded in the right-hand open reading frame (ORF) of the viral genome (46), whereas in members of the Dependovirus genus, including AAVs, all capsid proteins are encoded by the cap ORF and generated by alternative splicing of the mRNA and use an alternative translational start codon (47). The shared C-terminal sequence and structure suggest that VP1 and VP2 assemble with equivalent interactions to make the viral shell. In most viruses, the VP1 N-terminal region of the capsid structure contains a structural domain that contains a phospholipase A2 (PLA2) enzyme and a nuclear transport sequence (48,–55). The VP1 N termini of most viruses are enclosed within the capsid, whereas in the human B19 parvovirus, the larger sequence may be at least partially exposed to the outside (56). In experimental settings, including pH <6, heat (>37°C), or cation depletion (Ca2+ and Mg2+), the VP1 N terminus of MVM is extruded, suggesting that structural changes in the parvovirus capsid are highly dependent on the cellular conditions and the availability of ions (57). It is unknown how the VP1 proteins (and VP2 proteins of AAV) are distributed within the capsid, but they will introduce asymmetry of unknown form and relevance. About 20 residues of the VP2 N-terminal sequences of protoparvoviruses are exposed outside the capsid in DNA-containing (full) capsids, and about 80% of those (~40 to 45 of the ~50 to 55 VP2) may be cleaved off by proteinases, with the resulting VP3 N terminus being determined by the specific cleavage site of the protease(s) present (41). However, not all parvoviruses have this VP3 protein (58). The cleavage of VP2 to VP3 in full capsids may also play a role in facilitating DNA release and has been shown to alter the capsid infectivity of minute virus of mice (MVM) (59,–61). In AAV2, AAP promotes the assembly of VP3 into the capsids (62). The inference here is that VP2 of the protoparvoviruses (or VP3 of AAV) is responsible for capsid assembly and the virion stability. The role of VP2-to-VP3 cleavage in the protoparvovirus life cycle remains to be fully understood.
An elevated region surrounding the threefold axis has been defined as the threefold spike (21, 23), and in the AAVs, three structures around the threefold axis make separate spikes (27). A β-cylinder composed of five β-hairpins surrounds a pore located at each fivefold vertex, and a depressed region called the canyon encircles the fivefold cylinder in most viruses (23). Another depressed region (the dimple) spans the twofold axis (23).
Many parvovirus virions also contain metal ions, including Ca2+ within the protein capsid shell and Mg2+ associated with the packaged ssDNA genome (63, 64). At neutral pH, the Ca2+ sites in the capsids of CPV and feline panleukopenia virus (FPV) contain up to 3 or 4 ions per subunit, respectively (63). Mg2+ ions, on the other hand, may contribute to the relatively stable structure of the folded DNA inside the capsid (64). The degree of saturation of the potential Ca2+ binding sites under different conditions is unknown, and the different binding sites likely vary in occupancy under different conditions inside or outside the cells, which would introduce dynamic and asymmetric changes in the structure (41, 63). Potential interactions of the viral structure with other ions in host cells, differences in the cellular compartments where these ions might associate with or be removed from the capsid protein shell and the viral DNA, and the exact roles of these ions during infection remain unknown.
The viral genome is replicated by one or more host DNA polymerases, and simultaneously the newly formed DNA strand may be displaced and packaged into the preassembled capsid through one of the 12 fivefold pores. That viral genome packaging process occurs through the action of the helicase of the NS1 protein in the autonomous parvoviruses or Rep68 protein in AAV (65,–67). To get packaging of the DNA strand, it appears likely that the helicase oligomer must engage with the capsid around the entry portal to allow DNA threading and to overcome the back force that likely develops after a proportion of the viral genome has been packaged (68,–70). The mechanisms for NS1-capsid engagement have not been described, but presumably involve specific NS1 domain interactions with structures around the fivefold cylinder that makes up the pore (23). After viral genome packaging is finished, around 24 nucleotides of the ssDNA 5′ end remain outside the particle, and one of the NS1 or Rep proteins remains covalently bonded to the DNA terminus through the hydroxyl group of a tyrosine (71, 72). Endonucleases can cleave this exposed 5′ end of the ssDNA without affecting viral infectivity or replication (71). As previously stated, packaging the genome results in the exposure of most of the VP2 N termini to the exterior of the parvovirus capsid, where they can be cleaved by proteases to VP3 (41, 73). A number of the ssDNA bases also interact with internal VP residues, suggesting that the viral genome folds in a fairly structured manner and includes ordered DNA-capsid protein interactions (64).
HOST LIGAND INTERACTIONS WITH PARVOVIRUS CAPSIDS
Binding to attachment factors and cellular receptors and the process of infection.
Binding and interactions of parvovirus capsids with attachment factors and/or cellular receptors are likely critical first steps in the process of cell infection. Low-affinity attachment factors might help to tether virus particles to the cell surface until a high-affinity interaction with the primary receptor occurs, which leads the virion to enter an endosome, cross the plasma membrane barrier, and later enter the nucleus to get access to the essential host cell replication machinery. Both carbohydrates and proteins have been identified as attachment factors and/or cellular receptors depending on the specific parvovirus (74,–77).
Human parvovirus B19 replicates exclusively in human erythroid progenitor cells, and receptor binding appears to be complex (78,–81). While erythrocyte P antigen (globoside) has long been shown to be involved in cell attachment and infection, a number of cells with globoside on their surfaces are not susceptible to infection, which may be related in part to intracellular inhibition of viral transcription in nonerythroid cells (82,–84). Other protein-based receptors for parvovirus B19 have been identified, including Ku80 autoantigen, integrin α5β1, and tyrosine-protein kinase receptor UFO (85,–87), but this is still an area of active research.
A key receptor for many AAVs on cells is the AAV receptor (AAVR), a glycosylated IgG-domain-containing receptor, which binds different virus capsids through two different domains. AAVR appears to be a common receptor and host infection factor for all AAV serotypes, with the exception of AAV4, which is AAVR independent (88, 89). Cell culture-adapted AAV2 and AAV3 also bind to heparan sulfate proteoglycans (HSPGs) for low-affinity adherence to the cell surface and infection of host cells (90), although AAV2 variants that do not bind to HSPG are also infectious (91). Other receptors linked to AAV2 cellular infection include αVβ5 integrin and basic fibroblast growth factor receptor 1 (92), although some studies claim that V5 integrin is not involved (93). AAV4 and AAV5 bind sialic acids (Sias), with AAV4 binding α2-3-linked Sias and AAV5 binding both α2-3- and α2-6-linked Sias (94). AAV5 can also attach to and infect cells via platelet-derived growth factor receptors (5, 95). Virus infection might be mediated by a range of different cross-linking ligands, and AAVs could be modified to use a variety of alternative receptors by mutations or insertions within the capsid protein (6, 96, 97). Many other parvoviruses, including bovine parvovirus, H-1 parvovirus, porcine parvovirus, and minute virus of mice (MVM), also employ Sias as their primary cellular receptor (76, 77, 98, 99). CPV and FPV bind to Sia, and that appears to be exclusively to N-glycolyl neuraminic acid (NeuGC), which is found on the erythrocytes and cells of most cats, primates, and horses but not on the cells of most dogs (100). NeuGC binding is temperature and pH dependent and is controlled by residues at a depressed region (the dimple) on the viral capsid. Sia binding does not facilitate infection of tissue culture cells, but CPV mutants that do not bind Sia are frequently selected in experimental passages in cat cells. Capsid binding to terminal Neu5Gc may be important in regulating the host range for CPV and FPV (101).
CPV and FPV infect cells after binding to the transferrin receptor (TfR) type 1; structural and chemical differences between feline and canine TfRs directly influence viral attachment to cells (102, 103), and some changes in the virus or the receptor allow capsid binding but not infection (104). The binding of host-specific TfRs and their interactions with CPV and FPV capsids determine their host ranges (103), including the presence of an additional glycosylation of canine TfR via an asparagine at residue 384 (105, 106).
Antibody binding and neutralization.
The parvovirus capsid is a potent antigen, and the sites of anticapsid antibody binding to porcine parvovirus (PPV), waterfowl parvoviruses (WPV), B19, AAV, CPV, and FPV have been defined. In PPV, two monoclonal antibodies (MAbs) with neutralizing activity recognize linear epitopes on the VP2 protein (107). The MAb 5B5 can neutralize by binding a conserved linear epitope expressed on the VP3 protein of WPV, including goose parvovirus (GPV), novel GPV-related virus (NGPV), and Muscovy duck parvovirus (MDPV) (108). For the human B19 virus, antibodies directed to both the VP1 and VP2 capsid proteins bind to linear and conformational epitopes and neutralize infection at low molar concentrations (109).
In AAVs, many mouse monoclonal antibodies target residues on the threefold spike, which is involved in receptor binding (29, 110,–112). The AAVR binding site for AAV overlaps the epitope of a neutralizing monoclonal antibody, A20 (28), and overlap with the epitopes of other AAV2-neutralizing antibodies is seen, suggesting competitive inhibition of AAVR binding (29). For AAV5, there is significant overlap between the PKD1 binding site and the residues that interact with the neutralizing antibody ADK5b (29, 30).
For CPV and FPV, overlaps exist between the TfR binding site and many anticapsid monoclonal antibodies (26, 31). Furthermore, some naturally occurring mutations in CPV affect the binding and functions of both the receptor and antibody (38, 39, 113, 114). Antigenic variation in CPV- and FPV-related viruses occurs during natural evolution (115,–117), and escape mutations are selected by monoclonal antibodies (118, 119). These naturally occurring or experimentally selected escape mutations tend to fall within a small number of positions on the capsid surface (120, 121). Interestingly, despite low sequence identity in the parvovirus capsid antigenic structures from different parvovirus genera, some neutralizing antibodies recognize conserved antigenic regions, highlighting the high conservation of parvovirus capsid structures and their antigenicity (122).
REMAINING PUZZLE PIECES TO UNDERSTAND THE STRUCTURES AND FUNCTIONS OF PARVOVIRAL CAPSIDS
A number of questions remain unanswered, and those concern the capsid structures that govern infection, egress, and transmission and likely influence tissue tropism and host ranges. In particular, questions remain about the roles of submolar, asymmetrically arranged, or dynamic protein sequences or domains. In some cases, those will be due to protein cleavage or the addition or removal of ions. Here, we divide those unknown pieces into four sections: (i) DNA packaging and the role of the NS1/Rep68 and its capsid interaction, as well as the folded DNA structure and its interactions with the capsid and NS1/Rep68 proteins; (ii) the disposition of the VP1 and VP2 N termini, internal capsid protein cleavages, and VP processing and possible roles in infection; (iii) the interactions of the viral capsid and genome with metal ions; and (iv) the viral capsid interaction with receptors or antibodies and their effects upon binding (Fig. 1). In each section, we present a brief summary of the major structural components (Fig. 2) and highlight questions remaining to be answered.
Summary of the open questions in the parvovirus field addressed in this review. Listed are all the relevant unanswered questions. Diagrams are provided to graphically represent the structural components involved in each section. The review is structured focusing on four major areas: (i) DNA packaging and the role of the NS1/Rep68 and its capsid interaction, as well as the folded DNA structure and its interactions with the capsid and NS1/Rep68 proteins; (ii) the disposition of the VP1 and VP2 N termini, internal capsid protein cleavages, and VP processing and possible roles in infection; (iii) the interactions of the viral capsid and genome with metal ions; and (iv) the viral capsid interaction with receptors or antibodies and their effects upon binding.
Model of the structural features in the parvovirus capsid. Cartoon of the parvovirus capsid and essential structural features involved in cellular infection and host range. The negative-sense single-stranded DNA is represented in salmon, the capsid protein is in blue, NS1 in gray (Tewary et al. [131], PDB identifier [ID] 3WRQ), and ions (Mg2+ and Ca2+) in yellow and cyan, respectively. All other structural component details are labeled and highlighted. Each structural component presented here is only a visual representation of those features that remain to be determined in future work and that are highlighted in this minireview as open questions in the field.
DNA packaging and folding, defining the specific DNA-capsid interactions, and the potential NS1 helicase/nickase protein engagement with the capsid.
The parvoviruses and AAVs encapsulate their viral DNA in a preformed capsid. Members of the genera Parvovirus and Dependovirus can package either the positive or negative ssDNA strands; however, for some the (−) sense strand is predominantly packaged (123). The parvoviral genome is flanked by two inverted terminal repeats (ITRs) that may serve as viral origins of DNA replication and also provide the essential DNA packaging signals (124). Studies have shown that homotelomeric ITRs (e.g., AAV-ITR) could package both polarities of DNA into the preassembled capsid, whereas in heterotelomeric ITRs (e.g., MVM-ITRs) polarity is largely determined by the DNA resolution efficiency (19, 125, 126). The effectiveness of nick sites in the viral genome’s replication origin(s) also determines which DNA strand is packaged (127) and is needed for producing a functioning intranuclear transcription template and for effective progeny genome encapsidation (128).
The replicated viral genomes are packaged through one of the 12 pores situated at each of the capsid’s fivefold axes of symmetry, and this process is mediated by the ATP-dependent 3′-to-5′ helicase activity of the NS1 (in autonomous parvoviruses) or equivalent Rep protein (in AAV) by separating and packaging the newly synthesized strand during DNA replication by the host cell DNA polymerases (129, 130). The amino acid sequence alignment of the NS1 proteins of mink enteritis virus (MEV), MVM, CPV, FPV, porcine parvovirus (PPV), and AAV shows highest conservation of the active site sequences that control DNA packaging, indicating that those share structures and functions (19, 123, 126, 131,–133). Following the packaging of the majority of the genome, around 24 deoxyribonucleotides of the viral ssDNA 5′ end remain outside the particle, and as a by-product of the NS1 DNA-nicking reaction, one of the NS1 proteins remains covalently attached to the 5′ end of the viral DNA end through the hydroxyl group of a tyrosine (71, 72).
The viral capsid mechanical characteristics and structures change after the genomes are packaged (69). It is unclear whether the viral ssDNA folds into any specific form within the capsid, and the roles of the interactions between the packaged DNA and internal capsid residues are unclear, but there appears to be some specificity to the interaction, although no unique 60-fold interaction sequence has been revealed (64). There must be some flexibility in the interaction as both (+) and (−) strands can be efficiently packaged for many viruses (123), but the efficiency of packaging of genomes containing nonviral sequences is significantly reduced (127).
Any roles of the viral DNA’s externalized 5′ end and covalently associated NS1/Rep68 protein are unclear, and those may be a nonfunctional remnant of the packaging process (71, 72). After ~70% of the parvoviral viral genome has been packaged, downstream DNA threading is more energy consuming due to the back forces generated (68,–70). This also suggests that there is a specific engagement between the helicase/nickase domains of the NS1 or Rep68 proteins and the capsid, but any process for such an interaction is unknown (Fig. 3). It is also unclear how only a single genome is packaged into each capsid since packaging intermediates with multiple DNA insertions have not been described—whether this is due to stochastic effects, to capsids having a single distinct portal for packaging, or to some form of superpackaging exclusion is not clear for these viruses. It is also unknown how DNA packaging results in VP2 N terminus externalization, but the viral capsids must change during DNA packaging, so that one or more of those N termini are extruded to the outside of the capsid around the fivefold cylinder before or during DNA packaging.
Graphical representation of the NS1 oligomer-parvovirus capsid complex during negative-sense ssDNA packaging and folding. Diagram showing the surface of the parvovirus capsid and one of the fivefold axis pores involved in ssDNA packaging after capsid assembly (upper view). Five VP2 structural subunits are shown in different colors. A 90° rotation for a side view of that pore is provided to show the spatial relationship of the NS1 oligomer with the ssDNA (Santosh et al. [32], PDB ID 7JSI), the VP2 N termini, and the pore. The position of the NS1 oligomer and the interaction of Tyr with -OH are only a visual representation of the hypothesized engagement of the nickase/helicase functional domain with the viral capsid and the ssDNA during packaging and folding. The polymerase complex is not shown for a simplified visual overview of the process. The high-resolution CPV capsid structure (Lee et al. [162], PDB ID 6OAS) was reconstructed with Chimera X (Pettersen et al. [163]). The structural components presented here are only a visual representation of those features that remain to be determined in future work.
VP2 cleavage and processing as a requirement for productive cellular infection.
Parvoviral capsids assemble from 60 copies of two or more versions of a single viral protein (VP), VP1 to -4 depending on the species, which are numbered in ascending order of size, with VP1 being the biggest. As we mentioned above, these capsid protein products are produced by different translational mechanisms depending on the virus family, and those are assembled at different proportions; VP2 is the major capsid protein in protoparvoviruses, whereas VP3 is the major capsid protein in adeno-associated viruses (38, 39, 41,–43). All these capsid proteins share the same C-terminal sequence. Around 6 VP1 molecules are included in each virion from infected cells, and that proportion is likely determined by the amounts of VP1 and VP2 present in the cell when the capsid is assembled (41). Mass spectrometry analysis coupled with other biochemical approaches of intact AAV capsids showed that various ratios of VP1, VP2, and VP3 subunits were present in each capsid (134, 135). VP1 is required for viral infectivity because it includes a PLA2 enzyme domain that assists in endosomal release and the nuclear localization sequence that allows transport into the cell nucleus (48, 49). CPV and other parvoviruses have the VP1-specific domains inside their capsids; however, the human B19 virus appears to have the VP1 unique sequence exposed to the exterior, and B19 viral infectivity can be neutralized by anti-VP1 antibodies (56). How the VP1 subunits are positioned in each capsid is unclear, but there may be some clustering, as in some studies VP1 domains have been preferentially cross-linked to one another (56).
Another poorly understood feature seen in the CPV capsid is an apparent autocleavage of 10% to 20% of the capsid proteins between VP2 residues Asp269 and Cys270 (Fig. 4A and andB,B, upper panels). Replacing VP2 residue 270 with Ser hinders cleavage and results in a more stable, but noninfectious capsid (39). The cleaved position is buried within the capsid shell and appears inaccessible to external proteinases, suggesting that this is an autoproteolytic cleavage which activates the capsid for infection. It is possible that this cleavage will increase capsid flexibility essential for cell infection or allow some other function. AAV2 capsids have a similar cleavage site within the capsid protein, between residues Arg588 and Pro589 (VP1 numbering) (Fig. 4A and andB,B, lower panels), which is located near the capsid surface. In contrast, neither AAV1 nor AAV5 has the Arg588 cleavage site (136). If those VP cleavages are required for parvovirus capsids to become infectious, it is not known how many VP proteins must be cleaved.
Graphical representation of the viral capsid cleavage sites in CPV and AAV2. (A) Diagrams showing both the CPV VP2 sequence and the AAV2 VP1 sequence highlighting the location of the proteolytic cleavage sites. (B) Diagrams showing the proteolytic cleavage sites in a CPV VP2 subunit and in an AAV2 VP1 subunit, both in the context of the surrounding protein structure. Residues involved in the cleavage process are highlighted in different colors from the main amino acid chain, and the cleavage sites are indicated with a red dashed line (based on data from the work of Callaway et al. [39] and Van Vliet et al. [136], respectively). High-resolution CPV and AAV2 capsid loops (Lee et al. [162], PDB ID 6OAS, and Xie et al. [164], PDB ID 1LP3, respectively) were reconstructed with Chimera X (Pettersen et al. [163]).
Metal ion interactions with capsids.
Several viruses, including parvoviruses, exhibit pH-dependent Ca2+ binding, suggesting that the structure is influenced by pH changes as well as ion availability (63, 137). As mentioned above, FPV and CPV bind up to 180 or 240 Ca2+ ions per capsid. The functional significance is still unknown, and the binding and release appear to be reversible—which distinguishes these viruses from some other viruses where ion removal results in an irreversible change in the capsid structure (138). For some parvoviruses, this Ca2+ requirement appears to be critical for capsid degradation and genome release in the initial infection cycle (41, 57, 73, 130). For parvovirus B19 and MVM, depletion of capsid-associated divalent ions rendered the viruses unstable, and exposure to 37°C was sufficient to trigger DNA externalization without capsid disassembly (139, 140). However, for CPV and FPV, VP2 residues 359 and 375 are part of a flexible capsid surface loop involved in binding Ca2+, but whether those play roles in functions such as receptor binding, capsid destabilization, or genome release is still not understood (63). The specific timing of the association of these Ca2+ ions as well as their source within the infected cell or host is also unclear. For parvoviruses, it is unlikely that Ca2+ association occurs in the cytosol as that cellular compartment is calcium depleted (141,–143). Progeny parvoviruses may pick up Ca2+ from the nuclear envelope (NE), or once the capsid is released to the extracellular space (144) or, in the case of CPV and FPV, in the intestinal contents or the feces (145).
As described above, ssDNA packaging in parvoviruses is a highly energetic process. The association of Mg2+ ions with the viral DNA appears associated with the condensation and stabilization of the viral genome folding (64). The sources of these Mg2+ ions and their roles in genome processing and folding are unknown, but it is likely that these Mg2+ ions get copackaged with the ssDNA in the nucleus during genome packaging.
There are a number of open questions about the role of ions in the parvoviral functions. It is uncertain how many cations (likely Ca2+) are present within any single capsid shell or how significant any variation would be, but it is clear for CPV that when ions are removed the surface loops become more flexible (63). VP1 PLA2 activity activates Ca2+ entry in cells infected with parvovirus B19 (146); this role in modulating Ca2+ concentrations is unknown in other parvoviruses (144). Some viruses might hijack cellular Ca2+ signaling for initial entrance, viral structure stabilization, replication modulation, and effective progeny egress (147); however, this is unclear for parvoviruses. On the other hand, the function of Mg2+ in DNA packaging is likely important for stabilizing the genome, but that has not been investigated in detail. It is also unclear if the presence or removal of ions provides cues to the host and cellular processes such as receptor binding and endosomal acidification. There is evidence that AAV viral proteins interact with ions including Zn2+, Co2+, and Pb2+ for effective vector transduction (148), but the roles of ions in capsid structure or genome organization in AAV—and perhaps other parvoviruses—are not well understood. The answers to these questions will give information on how dynamic the capsid structure is, on how it changes before and after infection, on DNA packaging, and on what processes regulate genome packing and externalization during infection.
Receptor and antibody binding interactions: host range, overlapping binding sites, antigenic selection, and escape variants.
The surface of parvovirus virions is composed of 60 copies of a relatively small repeating structural unit that provides both the receptor and antibody binding interface. Parvoviruses must engage with host cell receptors, which are typically glycoproteins or glycans, to infect cells. AAVR, HSPG, integrins, and TfRs are among the glycoprotein receptors discovered (4, 88, 90, 92, 102). These receptors attach to exposed loops on parvovirus capsids via a variety of intermolecular interactions, including charge-charge interactions with HSPGs, or through specific protein-protein interfaces (including polar and nonpolar interfaces, hydrophobic contacts, H-bonds, and salt bridge formation), in the case of TfR (Fig. 5A) and AAVR (Fig. 5B). Some parvoviruses also bind to Sia as a key cellular receptor for internalization and infection (76, 77, 94). Sia chemical modifications play important roles in controlling for both tissue tropism and viral serotype specificity, where mutations in the viral capsid modify the capsid-receptor interactions altering tissue tropism or control host range (36, 94, 97, 101, 149).
Structure of the parvovirus and AAV capsids with their respective main cellular receptors and two neutralizing antibodies. (A) Reconstructed structure of the CPV capsid in interaction with the TfR apical domain through the threefold spike. We also show the interface between the TfR and the CPV capsid surface (structure solved by Hyunwook Lee from Susan Hafenstein’s lab [162], PDB ID 6OAS). (B) Reconstructed structure of the AAV2 capsid in interaction with the AAVR binding domain through the canyon around the fivefold axis. We also show the interface between the AAVR and AAV2 capsid surface (based on data from the work of Silveria et al. [30], PDB ID 7KPN). (C) Structure of the CPV and AAV2 capsids in complex with neutralizing antibodies Fab14 and A20, respectively (Organtini et al. [31], PDB ID 3JCX, and McCraw et al. [28], PDB ID P3J1S, respectively). Both neutralizing antibody binding sites overlap the receptor binding sites in each virus. All high-resolution structures were reconstructed with Chimera X (Pettersen et al. [163]).
Open questions regarding capsid binding to cellular receptors.
The complex interactions between parvovirus capsids and host cellular receptors and the wide range of receptor types reported leave some questions about the role of receptors in infection and the specific receptor-capsid interactions. It is unclear whether receptor binding serves only as a tethering mechanism leading to endocytosis or whether the receptor-capsid interactions also promote structural capsid alterations required for infection, at least for some viruses. In the case of CPV binding the TfR, infection is not proportional to the affinity of attachment to different host TfRs. Also, some capsid variants bind the TfR and enter the endosome, but do not infect the cell, indicating that structural transitions upon receptor binding are likely required for infection (38). The attachment of parvovirus B19 capsids to globoside receptors, on the other hand, causes the exposure of VP1u, which is required for virus uptake (84).
A number of host attachment factors and receptors have been defined for AAVs of various types (36). The AAVR binds different viruses through one of two domains, and those appear to interact with the same general region of the capsid (150). Many AAV capsids also can infect after binding Sia or HSPG, so there are multiple interactions associated with virus-host binding. It is still unclear whether there are capsid structural changes following AAVR and/or glycan binding and whether those are required for infection. Glycosylation of cellular protein-based receptors may also form structural barriers that parvoviruses must overcome to allow infection. This is seen in the case of CPV, where the canine TfR has an additional N-linked glycan within the apical domain in the region that also binds within the capsid surface of the canine-adapted viruses (105, 106).
Apart from the chemistry of the various parvovirus receptors, the dynamics of receptor attachment and occupancy are generally not well understood. There are likely consequences of binding of multiple receptors to the capsid which may have a significant impact on receptor binding kinetics and the infection outcome (38). It is unclear if there is any cooperative, steric inhibitory, or allosteric effect upon binding of the first receptor to the parvoviral capsid, as well as how many receptors or glycans must bind for the virion to be endocytosed and establish infection in the target cell. For CPV, the number of TfRs bound may differ depending on the type of TfR (38), which may play a role in determining host range and controlling parvoviral infections in the different hosts.
It is also possible that for some viruses lower-affinity attachment factors such as Sia may associate the virus particle with the cell surface until a high-affinity interaction with the primary receptor occurs to allow viral entrance and infection. In order to infect cells, AAV, CPV, and MVM enter the cells via endocytosis (137, 151, 152), mainly through the canonical clathrin-mediated endocytic pathway, but it is not fully understood whether other endocytic pathways are required for productive infection. For MVM, caveolin- and clathrin-independent carrier-mediated endocytosis has been also described for virion cellular uptake (153). Other groups have shown that micropinocytosis is also employed by PPV for both cellular entry and nuclear trafficking (98). In contrast, AAV2 requires endocytosis via the CLIC/GEEC pathway for productive infection (154).
Despite the fact that specific parvovirus capsid-receptor interactions have long been recognized as controlling host range and tissue tropism (36, 38, 97, 103, 104, 113, 114, 149), many aspects remain unclear. Variation in capsid structures, as well as chemical modifications in the receptor itself, is a variable that can impact virus-receptor interaction. The AAV serotype that infects a particular host is in many cases determined by the attachment of the viral capsid to a particular Sia variant or linkage (36). Changes to key FPV capsid residues in the receptor binding site were sufficient for the feline virus to jump into dogs and cause a worldwide pandemic (149). CPV has now been circulating in its native host and other mammals for over 45 years, and structural differences in the viral capsid are frequently associated with additional host-adaptive variations (114, 155). Despite the many interactions between parvovirus capsids and the many receptors, the details of the emergence and selection of these host range-associated mutations in the various hosts often remain unknown. It is also unclear how mutations that control host range impact other aspects of viral fitness and replication. Identifying these details will help explain the dynamics of emerging viruses that switch hosts to cause outbreaks. This will also aim to inform and leverage tailored AAV vector treatment in patients, for example, because engineering AAV to alter critical residues on the capsid surface may be enough to target particular tissues of interest.
Questions regarding capsid binding to antibodies.
Parvoviral capsids are potent antigens that elicit rapid and robust antibody responses that protect mammals against infection or which can inhibit AAV-based gene therapy vectors in vivo (156). However, details of the biology of the complex and dynamic interactions of parvovirus capsids with the antibodies produced remain unclear, including the definition of an epitope on the parvovirus capsid and the nature of immunodominant regions that preferentially bind and trigger antibody production. It is still unclear whether there are significant structural and evolutionary differences between parvoviruses that infect vertebrates, which therefore interact with antibodies, and those that infect invertebrates, which are not undergoing antibody selection.
Natural antigenic variation is often found in parvoviruses (29, 113, 117, 119, 157,–161), although its biological or epidemiological significance is generally not well understood, and the mechanisms that govern the emergence of antigenic variants are undefined. Some mutations in parvoviruses in nature may result in antigenic escape phenotypes, but it is unclear if these lead to evasion of the host antibody responses. It is also unknown whether constraints are present that determine which capsid residues lead to antibody evasion. Much structural and biological information about antibody responses against parvovirus capsids is still based on rodent-derived monoclonal antibodies; little is known about natural host polyclonal antibody responses, and it is not clear how diverse the antibody repertoires are after either natural parvoviral infection or vaccination. The answers to these questions will provide structural and evolutionary insights into the complex and dynamic interactions of parvoviral capsids with neutralizing antibodies. Understanding antigenic epitopes of parvoviruses, including AAVs, can thus provide critical information for the development of effective vaccines, as well as for engineering novel gene therapy vectors for use in patients who have antibodies against wild-type AAV strains, resulting in poor AAV vector gene therapy efficacy. Furthermore, it will give information on how viral capsid structures shift in the face of the host humoral response, and how this may influence essential viral activities, potentially resulting in the emergence of new antigenic variants that can evade preexisting immunity.
Overlap between receptor and antibody binding sites.
Overlap between the antigenic epitope and the receptor binding site has in some cases contributed to cross-species transmission, giving rise to closely related antigenic variants that also have altered host range (Fig. 5C) (29, 113, 149). Nonetheless, the interplay between the binding of receptors and antibodies is not well understood, in particular, whether there are tradeoffs between the two functions. Understanding the mechanisms of host recognition and the dynamics of the binding by antibodies and receptors would provide insight into the associations between antigenic and host range variation, enabling us to clarify mechanisms of antibody neutralization and to predict capsid structures that allow viruses to switch hosts or to escape host immunity.
CONCLUDING REMARKS
Despite all the advances in understanding parvovirus biology and architecture, many unanswered questions remain. These include uncovering the packaging and structure of the viral ssDNA and its specific protein interactions, identifying dynamic and/or asymmetrical features in the viral capsid, determining the interaction of the virus with nonprotein components such as metal ions, and understanding the complex interplay between cellular receptors and antibody binding on the viral surface. Understanding these functions will reveal the intricate mechanisms that these relatively small and simple viruses use to successfully sustain transmission, jump hosts, and overcome barriers, including the host immune system.
ACKNOWLEDGMENTS
This work was supported by the National Institutes of Health grants R01-AI092571 and R01-GM080533 to Colin R. Parrish, the NIH-Diversity Supplement 3R01AI092571-08W1 to Colin R. Parrish and Robert López-Astacio, and the Daversa Family Scholarship to Robert López-Astacio.
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