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Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.

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Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.

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Chapter 63Subversion of innate and adaptive immunity: immune evasion from antibody and complement

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Department of Medicine, University of Pennsylvania School of Medicine, PA, USA

Many herpesviruses encode immune evasion molecules that interfere with activities mediated by antibody and complement, suggesting the importance of antibody and complement in host defense against herpes infections. How does this observation reconcile with the clinical findings that severe infections develop mostly in subjects with T-cell deficiencies, such as transplant recipients or those with advanced HIV infection? An explanation that we favor is that T-cells assume a pivotal role in host defense partly because herpesviruses are very effective at limiting the activities of antibody and complement. Support for this hypothesis comes from experimental studies using mutant HSV-1 strains defective in antibody and complement immune evasion that demonstrate a marked increased in effectiveness of antibody and complement in host defense against the mutant viruses (Lubinski et al., 2002).

Newborns lack mature T-cell repertoires and generally have low serum complement levels; therefore, observations in human newborns provide opportunities to assess the contributions of antibodies independent of T-cells and perhaps complement in host defense against herpesviruses. The severity of HSV and CMV infection in the fetus and newborn are greatly reduced when the infection in the mother is recurrent rather than primary. In recurrent infection, antibodies pass transplacentally to the fetus and protect against the infection. Passive transfer of VZV antibodies from mother to fetus protects the newborn from severe chickenpox when exposed days to weeks after delivery. Similarly, treating newborns with varicella zoster immune globulin greatly reduces the severity of infection in infants born too soon after onset of chickenpox in their mothers to benefit from passive transfer of maternal antibodies. Therefore, lacking mature T-cells, newborns rely on passive transfer of maternal IgG antibodies to modify disease severity, suggesting that antibodies are partially effective against herpesviruses. The immune evasion strategies of herpesviruses target the IgG Fc domain, but do not inhibit neutralizing activities mediated by the IgG Fab domain, which likely accounts for the partial protection provided by antibodies.

Role of the herpesvirus IgG Fc receptor in immune evasion


Herpesviruses encode glycoproteins that bind the Fc domain of IgG, referred to as viral IgG Fc receptors (vFcγR). Table 63.1 lists the human herpesviruses that encode vFcγRs and the genes involved. Non-human herpesviruses, pseudorabies virus (PRV) and murine cytomegalovirus (MCMV), also express vFcγRs, suggesting that vFcγRs fulfill important roles in pathogenesis (Favoreel et al., 1997; Thale et al., 1994). FcγRs are detected on many micro-organisms, including staphylococci (protein A), streptococci (protein G), schistosomes, trypanosomes, hepatitis C virus (core protein), and coronaviruses (S peplomer protein). FcγRs are also detected on mammalian cells (cFcγRs) and regulate B-cell activation, phagocytosis (engulfing particles ≥1 μM), endocytosis, antibody-dependent cellular cytotoxicity (ADCC), and release of inflammatory mediators (Raghavan and Bjorkman, 1996). Below, we discuss the structure and function of vFcγRs and consider similarities with cFcγRs.

Table 63.1. IgG Fc receptors encoded by human herpes viruses.

Table 63.1

IgG Fc receptors encoded by human herpes viruses.

The IgG Fc domain mediates important antibody effector activities, including C1q binding, interacting with cFcγR on NK cells to trigger ADCC, phagocytosis and release of cytokines and proinflammatory molecules from granulocytes and macrophages. Figure 63.1 depicts an IgG molecule with its Fc domain showing the regions involved in C1q binding and interaction with cFcγRs or the HSV-1 vFcγR (gE-gI).

Fig. 63.1. Schematic drawing of the IgG molecule.

Fig. 63.1

Schematic drawing of the IgG molecule. Four immunoglobulin motifs are shown on the IgG heavy chains (black) and two on the IgG light chains (grey). Sites of interaction are shown between the IgG Fc domain and FcγRs on mammalian cells, C1q and (more...)

IgG Fc receptors on mammalian cells

Specific cellular Fc receptors interact with each of the immunoglobulin classes, IgA, IgD, IgE, IgG and IgM. However, only IgG Fc receptors have been detected on human herpesviruses; therefore, the discussion below focuses on cFcγRs.

Three classes of cFcγRs are present on mammalian cells, including FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16) (Fig. 63.2) (Raghavan and Bjorkman, 1996). FcγRI is detected on granulocytes (neutrophils, eosinophils and mast cells), monocytes and macrophages, and is a heterodimer consisting of one α-chain and two γ-chains. The α-chain contains three extracellular Ig-like domains. The membrane proximal domain is the region primarily involved in Fc binding activity. The γ-chains are linked by a disulfide bond and are necessary for cell signaling events and for expression of the α chain at the cell surface. The γ-chains contain amino acid sequences, referred to as ITAMs (immunoreceptor tyrosine-based activation motifs) that become phosphorylated at tyrosine positions upon cross-linking of the FcγR. The ITAMs trigger intracellular signaling events that are initiated by src family protein tyrosine kinases and that induce phagocytosis and endocytosis. FcγRI binds single IgG molecules (monomeric IgG) with high affinity (2 × 109−5 × 109 M−1). IgG complexes are required for efficient triggering of FcγRII and FcγRIII since these receptors bind monomeric IgG with low affinity (∼106 M−1).

Fig. 63.2. Schematic drawing of cellular FcγRs.

Fig. 63.2

Schematic drawing of cellular FcγRs. The FcγRs contain an α chain that has two or three Ig superfamily motifs (shown as ovals). The motif closest to the cell membrane (dark grey) functions as the IgG Fc binding domain. FcγR1 (more...)

FcγRII has two human isoforms, ⅡA and ⅡB. Both contain a single α-chain with two Ig-like extracellular domains. The membrane proximal domain is involved in Fc binding activity. The cytoplasmic domain of FcγRIIA contains an ITAM motif, while ⅡB has an ITIM motif (immunoreceptor tyrosine-based inhibitory motif) that inhibits cell activation. Receptors with ITIMs are found on neutrophils, macrophages, mast cells and B cells and contain sequences that are phosphorylated at a tyrosine position upon receptor cross-linking leading to inhibition of activation signals (Ravetch and Bolland, 2001).

FcγRIII in involved in ADCC (NK cell-mediated), phagocytosis and endocytosis. This receptor has two isoforms, ⅢA with a polypeptide chain anchor, and ⅡB with a glycophosphatidyly inositol (GPI) linkage. FcγRIIIA contains an α chain with two Ig-like extracellular domains, and a γ- or ζ-chain that contains ITAMs. FcγRIIIB has only an α-chain with two extracellular Ig-like motifs. IgG Fc interacts with the membrane proximal Ig-like domains of both FcγRIII isotypes. FcγRIIIA is found on macrophages, mast cells and as the only FcγR on NK cells, where it mediates ADCC, while ⅢB is detected on neutrophils.

Herpes simplex virus FcγR

Both HSV-1 and HSV-2 encode vFcγRs, although considerably more is known about the structure and functions of the HSV-1 FcγR, which is discussed below.

gE and gI structure

Glycoproteins gE and gI form a heterodimeric complex that contains one molecule each of gE and gI and that functions as an FcγR (Chapman et al., 1999; Johnson et al., 1988). HSV-1 gE strain 17 has a molecular mass of ∼80 kDa and is a 550 amino acid type 1 transmembrane glycoprotein, although strain NS, used extensively in the authors’ laboratory, encodes two additional amino acids, glycine and glutamine, at positions 186 and 187 respectively (Lin et al., 2004). The NS strain gE ectodomain includes 421 amino acids with a predicted signal sequence from amino acids 1–23, two N-linked glycosylation sites, a transmembrane domain (422–446), and a large cytoplasmic tail (447–552) that undergoes serine phosphorylation (Edson et al., 1987).

HSV-1 strain 17 gI has a molecular mass of ∼70 kD and contains 390 amino acids. Sequences of strains KOS and NS differ from strain 17 in that a 7-amino acid repeat at position 225–231 in strain 17 is absent in KOS and NS (H. M. Friedman, unpublished observations). HSV-1 strain NS gI has a predicted signal sequence from amino acid 1–20, three N-linked glycosylation sites, a transmembrane domain (267–287), and a large cytoplasmic tail (288–383).

Glycoprotein gE binds Fc in the absence of gI, while gI cannot bind Fc without gE. The gE-gI complex binds Fc with higher affinity than gE alone (Bell et al., 1990; Dubin et al., 1990). IgG monomers bind to the gE–gI complex with an affinity of 0.4 × 107 − 2 × 107 M−1, while gE binds IgG aggregates, but not IgG monomers (Chapman et al., 1999; Dubin et al., 1990). Approximately 4 × 106 vFcγR binding sites are present on HSV-1 infected cells in vitro, which exceeds the number of cFcγR detected on human leukocytes by ∼100-fold (Johansson and Blomberg, 1990). The HSV-1 FcγR binds human IgG4 with higher affinity than IgG1 or IgG2, while IgG3 fails to bind (Johansson et al., 1984). A substitution of arginine for histidine at IgG4 Fc amino acid 435 abolishes Fc binding to gE-gI, which is consistent with the observation that most human IgG3 allotypes contain an arginine at Fc position 435 (Chapman et al., 1999). IgG subclass concentrations in serum are age dependent, but in general, IgG1 is most abundant, followed by IgG2, with considerably lower concentrations of IgG3 and IgG4. IgG1 and IgG3 are potent activators of complement, while IgG2 is slightly less so, and IgG1 binds to FcγRIIIA on NK cells to mediate ADCC (Ghirlando et al., 1995). Therefore, by interacting with IgG1 and IgG2, the vFcγR is binding the two most abundant IgG subclasses and potentially interfering with complement activation and ADCC mediated by these subclasses.

Mapping studies have determined that gE amino acids 24–211 are required to form a complex with gI, while gI amino acids 43–192 interact with gE (Basu et al., 1995; Rizvi and Raghavan, 2001). Two approaches were used to define regions on gE involved in Fc binding. Fragments of gE DNA were fused to HSV-1 gD DNA and expressed in mammalian cells. The smallest gE fragment to retain FcγR activity included gE amino acids 183–402 (sequences based on strain 17) (Dubin et al., 1994). Linker insertion mutagenesis was used as a second approach to evaluate gE domains involved in FcγR activity. Four amino acid inserts at each of ten positions between gE amino acids 235–380 eliminated IgG Fc binding. Therefore, the results of the two approaches were complementary, establishing the gE domain between amino acids 183 and 402 as sufficient for Fc binding, while mutations between amino acids 235 and 380 resulted in loss of function. The crystal structure has been solved for the interaction of the IgG Fc fragment with a soluble form of cFcγRIII (Sondermann et al., 2000). Five contact sites were identified on the cFcγR over a linear range of 73 amino acids, suggesting that the much broader linear range of gE mutations that resulted in loss of function likely reflect changes in conformation and contact sites. This conclusion is supported by a low-resolution crystal structure of the gE–gI/Fc complex that was solved at 5 Å (Sprague et al., 2006). The crystal structure was verified by a theoretical prediction model of gE–Fc interaction that was based on the crystal structure of the gE C-terminal ectodomain (CgE amino acids 213–390) solved at 1.78 Å. The gE–gI/Fc crystal structure demonstrates that two gE-gI molecules interact with one Fc dimer and predicts that Fc interfaces with gE amino acids 225, 245–247, 249–250, 256, 258, 311, 316, 318–322, 324 and 338–342. Loss of Fc binding when gE is mutated at other sites likely occurs because of changes in gE conformation.

The HSV-1 FcγR and immune evasion

An IgG antibody molecule that is directed against HSV-1 can bind by its Fab domain to viral antigens on the virion or infected cell while the Fc domain of the same antibody molecule binds to the vFcγR (Fig. 63.3) (Frank and Friedman, 1989). Antibody bipolar bridging is used to describe this form of antibody binding, which requires considerable flexibility of the IgG molecule at the hinge region. Studies of the dynamic conformations of IgG in solution and bound to receptors confirm IgG has the flexibility to mediate bridging (Zheng et al., 1992). The crystal structure of the gE–gI/Fc complex is also compatible with antibody bipolar bridging (Sprague et al., 2006). Antibody bridging is postulated to be an important immune evasion strategy, since the vFcγR binds the Fc domain of antibody molecules that are targeting the virus. The affinity of the HSV-1 FcγR for Fc is ∼100-fold lower than that of cFcγR1; therefore, binding of monomeric, non-immune IgG is limited. The IgG Fab domain binds with high affinity to the target antigen, which anchors the IgG Fc domain onto the virion or infected cell surface. The vFcγR is then able to bind the IgG Fc domain to block its activities.

Fig. 63.3. Schematic drawing of antibody bipolar bridging.

Fig. 63.3

Schematic drawing of antibody bipolar bridging. The IgG Fab domains bind to the viral antigen and the Fc domain of the same antibody molecule binds to the vFcγR (gE-gI).

Figure 63.1 shows the regions on Fc that interact with host and viral proteins. The region on IgG that binds to cFcγRs is located at the lower portion of the hinge region and the upper margin of the CH2 domain (Sondermann et al., 2000). The IgG Fc CH2 domain interacts with C1q to initiate complement activation, while the CH2–CH3 interface of the Fc domain binds to gE–gI, which is similar to the site of interaction between protein A and Fc (Johansson et al., 1989; Miletic and Frank, 1995). Despite the distance between domains on Fc involved in binding to gE–gI, C1q and cFcγRs, the HSV-1 FcγR is effective at blocking functions mediated by these regions of the Fc molecule (Dubin et al., 1991).

Studies were performed to assess the role of the vFcγR in pathogenesis. A mutant HSV-1 strain was produced by introducing 4 amino acids at gE position 339 (based on the sequence of strain 17). The mutant virus expressed gE and gI at the infected cell surface, but failed to bind IgG Fc measured by rosetting assays using IgG-coated erythrocytes and by flow cytometry using biotin-labeled non-immune human IgG (Nagashunmugam et al., 1998). Wild-type, gE mutant and gE-restored viruses were injected into the murine flank to assess the contribution of the vFcγR to virulence. The Fc domain of murine IgG does not bind to the HSV-1 FcγR; therefore, the three virus strains were expected to cause similar disease in mice, which was the observed result (Johansson et al., 1985; Nagashunmugam et al., 1998). Human IgG does bind to the HSV-1 FcγR; therefore, passive transfer of HSV antibodies was predicted to be more active against the vFcγR defective strain than against wild-type or restored virus. When infection was performed one day following passive transfer of HSV IgG antibodies, approximately 100-fold higher titers of gE mutant virus were required to cause the same level of disease as wild-type or restored virus. Passive transfer of non-immune human IgG or murine HSV IgG antibodies showed no differences among the various strains. Therefore, these in vivo studies define a contribution of the vFcγR to pathogenesis that depends upon the ability of the virus to block activities mediated by the IgG Fc domain. Synergy between gC and gE in mediating immune evasion was demonstrated in vitro and in vivo using an HSV-1 mutant virus defective in C3b and IgG Fc binding (Lubinski et al., 2002). Glycoproteins gC and gE interfere with complement activation at different steps in the cascade, which likely contributes to the synergy.

Additional mechanisms have been proposed for vFcγR-mediated immune evasion. The vFcγR promotes capping of viral antigens on the surface of infected cells in response to human HSV antibodies (Rizvi and Raghavan, 2003). The antibodies promote virus spread cell-to-cell when gE is expressed on the cell surface, which suggests that when antibodies are present, gE enables the virus to remain intracellular to avoid neutralization. In separate studies, the binding of Fc to gE-gI was noted to be pH dependent (Sprague et al., 2004). Binding of Fc occurs at an affinity of 2 × 107 − 3 × 107 M−1 at pH 7.4, which is the pH at the cell surface. In contrast, no binding occurred at pH 6.0. Based on antibody internalization studies described below, the results suggest that the vFcγR may internalize IgG and then dissociate within acidic intracellular compartments promoting degradation of antibodies. The crystal structure of the gE–gI/Fc interaction predicts that histidines at gE position 247 and Fc positions 310 and 435 are likely involved in Fc dissociation from gE at acidic pH (Sprague et al., 2006).

Human CMV FcγR

Cells infected with human CMV (HCMV) express ∼106IgG Fc receptors per cell that have an association constant of 2 × 108 M−1 (Antonsson and Johansson, 2001). Two HCMV vFcγRs have been reported (Atalay et al., 2002; Lilley et al., 2001). The first is a 234-amino acid type 1 transmembrane glycoprotein that migrates with an apparent molecular mass of 34 kDa (gp34) and has three potential N-linked glycosylation sites in the ectodomain (Lilley et al., 2001). The glycoprotein is encoded by TRL11 and IRL11, which are identical copies of a gene found in the terminal and internal repeats of the HCMV DNA long fragment. The cytoplasmic tail of gp34 has 31 amino acids and contains a conserved dileucine motif that is postulated to participate in IgG endocytosis. Sequence similarities were detected between gp34 and domain 2 of cFcγRII and Ⅲ (Atalay et al., 2002). The other HCMV FcγR is encoded by the UL119–118 open reading frame that produces a 347 amino acid type 1 transmembrane glycoprotein with a molecular mass of 68 kDa (gp68) (Atalay et al., 2002). The glycoprotein has 12 potential N-linked sites and an immunoglobulin supergene family-like variable domain that shares sequence homology with cFcγRI domain 3 (Atalay et al., 2002). The cytoplasmic tail has a possible modified ITIM-like motif (WSYKRL) that may be involved in cell signaling events. The lack of laboratory animal models for HCMV has hampered attempts to define the role of the HCMV FcγRs in pathogenesis.

Varicella zoster FcγR

The VZV US8 gene encodes gE, which functions as an FcγR on infected human cells (Litwin et al., 1992). Glycoprotein gE is a 623-amino acid type 1 transmembrane glycoprotein that has a signal sequence of 24 amino acids, a 544-amino acid extracellular domain with three predicted N-linked glycosylation sites, a 17-amino acid transmembrane domain and a 62 amino acid cytoplasmic tail. Binding of IgG Fc to gE initiates endocytosis, unloading the IgG cargo in lysosomal vesicles and subsequent recycling of gE to the cell surface (Olson and Grose, 1997). Endocytosis requires the gE cytoplasmic tail, and is mediated by tyrosine phosphorylation of a YAGL endocytosis motif (Olson and Grose, 1997). VZV gE shares sequence similarities with HSV gE, but not with cFcγRs (Litwin et al., 1992). Similar to HCMV, the in vivo relevance of the VZV FcγR in immune evasion has not been determined because of the lack of animal models.

vFcγRs on non-human mammalian herpesviruses

Murine CMV

The m138 (fcr-1) gene of MCMV encodes a vFcγR that has a molecular mass of 88 kDa and is a 569 amino acid type 1 transmembrane glycoprotein. The protein has a predicted signal sequence of 17 amino acids, a transmembrane domain from amino acids 535–552, 10 potential N-linked glycosylation sites, and a 17 amino acid cytoplasmic tail (Thale et al., 1994). Studies were performed to assess the function of the vFcγR in its natural host by preparing a mutant virus deficient in the fcr-1 gene and a revertant strain (Crnkovic-Mertens et al., 1998). The fcr-1 deficient strain showed normal replication kinetics in vitro, but significantly reduced replication in vivo. To determine if the reduced replication in vivo was caused by increased susceptibility to antibody, mutant and revertant strains were injected into B cell deficient mice. The expectation was that the two strains would have similar replication patterns in antibody deficient mice; however, this did not occur, suggesting that the vFcR had little or no role in pathogenesis. While this conclusion is potentially correct, other explanations are also possible. For example, to demonstrate a role for the HSV-1 FcγR in pathogenesis, small deletions were made in gE to abolish Fc binding without interfering with virus spread, another activity mediated by gE (Nagashunmugam et al., 1998). A similar approach may be required to assess the potential role of the MCMV vFcγR in pathogenesis.

Pseudorabies virus

PRV gE and gI form a molecular complex that functions as a vFcγR (Favoreel et al., 1997). PRV US8 encodes gE, a 62 kD type 1 transmembrane glycoprotein containing 577 amino acids, including an extracellular domain of 428 amino acids, a transmembrane domain of 26 amino acids, and a cytoplasmic tail of 123 amino acids (Klupp et al., 2004). PRV US7 encodes gI, which is a type 1 transmembrane glycoprotein containing 366 amino acids, including an extracellular domain of 285 amino acids, a transmembrane domain from amino acid 286–308, and a cytoplasmic tail of 58 amino acids (Klupp et al., 2004).

Studies performed in swine kidney cells demonstrate that PRV-specific antibodies induce capping of viral glycoproteins followed by their extrusion from the cell surface (Favoreel et al., 1997). Phosphorylation of two tyrosine motifs in the gE cytoplasmic tail are required for glycoprotein capping (Favoreel et al., 1999). Studies of PRV in swine monocytes, which are infected by PRV during natural infection, demonstrate that antibodies induce endocytosis of viral glycoproteins with co-internalization of MHC class Ⅰ proteins (Favoreel et al., 2003). Endocytosis removes viral glycoproteins from the cell surface and reduces the effectiveness of antibody dependent complement lysis of infected cells. Endocytosis is not uniquely mediated by gE-gI, but the vFcγR contributes to this activity (Van de Walle et al., 2003).

Summary of vFcγR studies

Activities mediated by the vFcγRs of human and non-human herpesviruses can be summarized as follows. First, antibody bipolar bridging is an important mechanism used by vFcγRs to protect the virus and infected cell against activities mediated by the IgG Fc domain, including complement activation and ADCC. Second, some vFcγRs mediate antibody capping, while others promote antibody internalization. In acidic intracellular compartments, antibodies may dissociate from the vFcγR and degrade, while the vFcγR recycles to the cell surface. Third, potential ITIM motifs have been noted on some vFcγRs that may regulate responses to antibody. Fourth, the HSV-1 FcγR is a virulence factor, reducing the effectiveness of antibodies in vivo.

Role of the herpesvirus complement receptors in immune evasion


The complement system plays an important role in both the innate and adaptive immune responses to viral infection. Activation of complement early following viral infection relies on the presence of highly specific recognition proteins, which have evolved to recognize and bind pathogen associated molecular patterns (PAMPs). These pattern recognition proteins include natural antibodies (IgM), C1q, C-reactive protein, mannan-binding lectin, and ficolins H and L. IgG and IgM antibodies are able to trigger the activation of complement following induction of specific humoral immune responses.

Complement is activated by one of three different pathways: classical, mannan-binding lectin (MBL), or alternative (Fig. 63.4). The classical complement pathway was the first pathway to be identified, and is normally considered to be antibody-dependent. Activation of the classical pathway occurs when the first component of the pathway, C1, binds the Fc region of either natural antibody or specific IgG antibody in complex with viral antigen. The classical pathway is also triggered in an antibody-independent manner when C1 binds directly to virions or infected cells.

Fig. 63.4. Sites of interaction between herpesviruses and the complement cascade.

Fig. 63.4

Sites of interaction between herpesviruses and the complement cascade. The boxed type identifies the sites in the complement cascade inhibited by viral proteins or by host-derived cellular proteins captured by viruses.

Activation of the MBL pathway is antibody-independent and occurs when one of the C-type lectins, MBL, ficolin H, or ficolin L recognizes carbohydrate structures on the surface of pathogens. The alternative complement pathway was originally described as the antibody-independent pathway (the MBL pathway was identified much later). Activation of the alternative pathway is spontaneous as a continued low-level release of the internal thioester bond of C3 allows it to bind to a wide range of “foreign” sites. The diversity of serum recognition proteins able to recognize and activate complement allows the complement system to protect against a wide variety of microbial pathogens.

Recently a fourth pathway for complement activation was described that involves SIGN-R1, a C-type lectin detected on marginal-zone macrophages in the spleen. The unique feature of this pathway is that SIGN-R1 binds C1q and activates the classical complement pathway in the absence of immunoglobulins. SIGN-R1 also binds the capsular polysaccharide of S. pneumoniae, and perhaps carbohydrates on other microbial pathogens, leading to C3 deposition on the organism and enhanced innate resistance to infection (Kang et al., 2006).

Activation of the complement cascade leads to numerous effector functions that result in neutralization and elimination of virus, thereby limiting spread, infection and disease. These include neturalization of viral particles, phagocytosis of complement-opsonized virus and virus-infected cells, direct lysis of virus and infected cells by the formation of pores known as the membrane attack complex, induction of inflammation, and enhancement of the adaptive immune response.

Regulation of complement

Given the complexity of the complement system, with over 30 complement proteins involved in activating the three divergent complement pathways, proper control is imperative. Regulation of the complement systems is necessary to prevent inappropriate activation and injury to bystander cells. Therefore, complement is tightly regulated by proteins present in serum and expressed on the surface of cells. These complement regulatory proteins include C1 inhibitor, CD59, and a class of proteins referred to as regulators of complement activation (RCA). RCA proteins include secreted plasma factor H, C4-binding protein and membrane bound complement regulatory proteins 1, 2, 3 (CR1, CR2, CR3), membrane cofactor protein (MCP) and decay accelerating factor (DAF) (Carroll, 2000; Da Costa et al., 1999; Spear et al., 1995; Spiller et al., 1997). Both CR2 and DAF are GPI-linked.

RCA proteins are homologous in structure, characterized by the presence of motifs known as short consensus repeats (SCRs). SCR motifs contain approximately 58 to 66 amino acids, with four conserved cysteine residues disulfide linked (cys 1 to 3, and cys 2 to 4) and several hydrophobic residues. SCR motifs are highly conserved, sharing 30%–40% amino acid identity. However, the number of SCRs contained within RCA proteins is highly variable, for example, both MCP and DAF contain four SCRs, while CR1 contains 30.

As the complement system plays an important role in host defense against viral infection, not surprisingly, viruses have evolved numerous mechanisms to control complement. Strategies employed by viruses fall into three categories: (1) viral proteins which are homologous to mammalian complement regulatory proteins; (2) viral proteins which have no sequence homology, but which share functional characteristics with complement regulatory proteins; and (3) viruses that incorporate host complement regulatory proteins into their envelope during viral maturation and egress.

Strategies employed by human herpesviruses to evade complement immunity

Viral proteins homologous to human complement regulatory proteins: Kaposi’s sarcoma associated herpesvirus complement control protein

Sequencing of the Kaposi’s sarcoma associated herpesvirus (KSHV) genome indicated that one gene, KSHV open reading frame 4 (ORF4), encoded a protein displaying a high degree of homology to many complement regulatory proteins, including RCA proteins DAF and MCP (Neipel et al., 1997; Russo et al., 1996). The KSHV ORF4 was predicted to encode a protein of 550 amino acids residues, with the first 270 amino acids forming four SCRs sharing 24.7% identity with DAF (Spiller et al., 2003b).

Characterization of transcripts produced by KSHV ORF4 indicated that three transcripts were produced, one full length, and two smaller, alternatively spliced forms (Spiller et al., 2003b). All three protein isoforms contained the four amino-terminal SCRs and transmembrane regions, not a GPI anchor present in DAF, and collectively, are referred to as KSHV complement control protein (KCP) or kaposica (Mullick et al., 2003; Spiller et al., 2003b).

Functional studies indicated that all three forms prevented C3 deposition on cell surfaces (Spiller et al., 2003b). Addition of a soluble form of each KCP isoform accelerated the decay of the classical pathway C3-convertase (Spiller et al., 2003a). All three forms of soluble KCP also accelerated the decay of the alternative pathway C3-convertase; however, they were 1000-fold less efficient than DAF, indicating that KCP mainly affects the classical pathway C3-convertase.

KCP acts as a cofactor for factor I (fI) mediated cleavage and inactivation of C3b and C4b (Mullick et al., 2003; Spiller et al., 2003a). KCP results in fI mediated cleavage of C4b to C4d, when both soluble and cell bound. KCP also acts as a cofactor for fI mediated cleavage of C3b to iC3b, and induces cleavage of iC3b to C3d, the only viral protein shown to date to do so. Binding affinity of KCP is higher for C4b than C3b, which may explain differences in the ability of KCP to degrade the classical and alternative pathway C3-convertases.

Viral proteins with no sequence homology, yet functional similarities with human complement regulatory proteins

HSV-1 and HSV-2 glycoprotein gC

HSV-1 and HSV-2 encode gC, a viral complement control protein that inhibits complement activation by binding C3b (Friedman et al., 1984; Kostavasili et al., 1997). gC of HSV-1 (gC-1) was the first complement control protein identified, and has been extensively characterized. Both gC-1 and gC-2 are rarely absent from clinical isolates, underscoring their importance in vivo. Moreover, gC is well conserved among members of the alpha-herpesvirus family, with homologues present in VZV, PRV, bovine herpesvirus 1 (BHV-1), and equine herpesviruses 1 and 4 (EHV-1, EHV-4). Despite this high degree of sequence conservation among alphaherpesviruses, gC displays little sequence homology with known complement regulatory proteins.

gC-1 and gC-2 are encoded by the UL44 gene and are type Ⅰ membrane glycoproteins of 511 and 480 amino acids respectively, which are expressed on virions and infected cells. Both are highly glycosylated with 9 and 7 N-linked glycosylation sites respectively (Rux et al., 1996). gC-1 also contains several O-linked glycosylation sites, localized to the amino terminus of the protein; gC-2, however, is not O-linked glycosylated. gC-1 and gC-2 share eight highly conserved cysteines, the disulfide bonding pattern of which has been determined for gC-1, and is likely similar for gC-2 and the gC homologues from other herpesviruses (Rux et al., 1996).

gC of both HSV-1 and HSV-2 binds C3b in a purified form and when expressed on the surface of transfected cells (Eisenberg et al., 1987; Tal-Singer et al., 1991). However, only HSV-1 infected cells express gC that is able to bind C3b (Friedman et al., 1984). Cells infected with HSV-2 display no C3b receptor activity (Friedman, 1986; Friedman et al., 1984). Lack of binding to C3b appears unrelated to affinity of gC-2 for C3b, as optical biosensor technology indicates that gC-2 has a tenfold higher affinity for C3b compared with gC-1 (Rux et al., 2002). One possible explanation may be that other host cell membrane components or viral glycoproteins expressed on the HSV-2 infected cell surface may interfere with the ability of gC-2 to bind C3b.

Both gC-1 and gC-2 bind C3 and its activation products C3b, iC3b and C3c (Kostavasili et al., 1997; Tal-Singer et al., 1991). This binding is mediated by C3b regions, which are well conserved in both glycoproteins. Four regions in gC-1 and three in gC-2 were identified by site-directed and linker insertion mutagenesis, with binding phenotypes confirmed in rosetting assays using C3b-coated sheep erythrocytes (Hung et al., 1992; Seidel-Dugan et al., 1990).

Functional studies indicate that gC-1 prevents complement-mediated neutralization of HSV-1 by binding C3b, thereby inhibiting activation of the classical complement pathway (Friedman et al., 1996; Harris et al., 1990). Evidence suggests that gC-2 may function in a similar manner (Gerber et al., 1995). Neutralization of HSV-1 in the absence of gC-1 is mediated by a C5 dependent mechanism that does not require viral lysis, aggregation, or prevention of viral attachment (Friedman et al., 2000). Complement likely interferes with HSV infection at a stage following viral attachment, for example, during virus entry or uncoating (Friedman et al., 2000).

gC-1 also prevents complement-mediated cell lysis of HSV-1 infected cells by accelerating the decay of the alternative pathway C3 convertase, C3bBb (Fries et al., 1986; Harris et al., 1990). The half-life of the C3bBb complex is extended three- to four-fold by the binding of properdin to C3b in the convertase. gC-1 contains a properdin interacting domain, localized to the amino-terminus, which interferes with the binding of properdin to C3b, destabilizing the C3 convertase (Hung et al., 1994; Kostavasili et al., 1997). By interfering with properdin’s ability to bind C3b, gC-1 prevents activation of the alternative complement pathway. This prevents lysis of HSV-1 infected cells.

gC-1 also contains a C5 interacting domain which prevents C5 from binding C3b (Fries et al., 1986). gC-1 thus interferes with activation of both the classical and alternative complement pathways, limiting neutralization of both virus and lysis of virus-infected cells. While both gC of HSV-1 and HSV-2 prevent complement-mediated neutralization of HSV virions, differences do exist. Only gC-1 is able to disrupt the activation of alternative pathway C3 convertase (Fries et al., 1986; Kostavasili et al., 1997). Moreover, the region of gC-1 important in blocking the binding of C5 and properdin to C3b is absent in gC-2.

Studies comparing the importance of both complement interacting domains of gC-1 were evaluated both in vitro and in an in vivo model of HSV pathogenesis (Lubinski et al., 1999). Complement neutralization experiments performed with a low passage clinical isolate that had been mutated within the C3 binding domain, the C5 and properdin blocking domain, or both, indicated that while both domains were important, elimination of the C3 binding domains significantly diminished the ability of gC to modulate complement (Lubinski et al., 1999). Similar results were seen in vivo in a murine model of HSV pathogenesis. HSV-1 was mutated in the C5 and properdin blocking, the C3 binding, or both domains (double mutant). Each mutant virus was significantly more attenuated than the wild type HSV-1 virus (Lubinski et al., 1999). That the C3 binding domain mutant was as attenuated as the gC double mutant indicated that the C3 domain is more important than the C5 and properdin in modulating complement activity.

EBV complement regulatory activity: unidentified protein

In addition to gC of HSV-1 and HSV-2, evidence suggests that Epstein–Barr virus (EBV) encodes a complement regulatory protein displaying no sequence homology with known human complement regulatory proteins. EBV virions derived from either marmoset or human B lymphoblastoid cells maintains complement regulatory activities (Mold et al., 1988). Incubation of purified EBV with immune human serum resulted in the cleavage of C3 into the inactive C3c. In addition, EBV functions as a cofactor for the Factor I mediated cleavage of C3b and iC3b and C4b and iC4b. No degradation occurred in the absence of Factor I. EBV accelerates the decay of the alternative, but not the classical C3 convertase. The EBV envelope protein responsible for this complement regulatory activity remains unknown. No virally encoded proteins with homology to known complement regulatory proteins have been identified; therefore, cellular proteins incorporated into the virion are possibly mediating this effect.

Viruses that incorporate human complement regulatory proteins into their envelope during viral maturation and egress: human CMV

HCMV-infected cells remain susceptible to antibody-mediated complement cytolysis for only a brief time following acute infection, suggesting that the cells are protected from complement lysis. Analyses of the complete genomic sequence of HCMV revealed no homologues of known complement regulatory proteins, and HCMV does not appear to encode a C3 binding protein (Smiley and Friedman, 1985). It was hypothesized that HCMV may alter the expression of host-encoded complement regulatory proteins in order to interfere with complement (Spiller et al., 1996). Candidates included DAF, MCP, and CD59, since each are expressed on uninfected cells that are permissive to infection by HCMV.

Studies examining the cell surface expression of both DAF and MCP by HCMV infected human foreskin fibroblasts indicated that levels were enhanced at 24, 48, and 72 hours post infection compared with mock-infected controls. Maximal expression was seen 72 hours post infection with a 3.4-fold and 8-fold increase in MCP and DAF respectfully. Expression of CD59, however, remained relatively stable (Spiller et al., 1996).

Incubation of HCMV virions with complement alone consumed complement activity and resulted in C3 deposition on the surface of the virion, yet resulted in negligible amounts of C9 deposition and no loss of viral infectivity (Spiller et al., 1997). These data suggest that HCMV is able to regulate complement and accomplishes this by interfering with the complement system upstream of C9 activation. Studies examining the expression of MCP, DAF, and CD59 on HCMV virions produced in human foreskin fibroblasts indicated that the three complement regulators were captured by the virion during egress and maturation (Spear et al., 1995; Spiller et al., 1997).

The mechanism by which MCP, DAF, and CD59 become incorporated within the HCMV virion remains unknown. Incorporation could represent a passive capture of upregulated plasma membrane proteins, as levels of both DAF and CD59 are increased during HCMV infection and are readily incorporated into foreign membranes (Spiller et al., 1996). Moreover, the distribution of both DAF and CD59 expressed on the surface of the virion correlates roughly with levels of each detected on the surface of the host derived cells, indicating that virions may obtain the host cell derived complement regulatory proteins in a passive manner (Spear et al., 1995). Incorporation, however, could be an immune evasion strategy adopted by HCMV, in order to protect virions and virus infected cells from complement-mediated neutralization. Treatment of HCMV virus with an anti-DAF antibody, not anti-CD59, reduced HCMV infectious titer in the presence of complement, indicating that DAF interferes with complement-mediated neutralization of HCMV virus (Spear et al., 1995).

Strategies employed by non-human mammalian herpesviruses to evade complement immunity

Viral proteins homologous to mammalian complement regulatory proteins

Murine gammaherpesvirus 68: MHV-68 RCA

Murine Gammaherpesvirus 68 (γHV68) gene 4 product is a complement regulatory protein, with significant homology to both virally encoded and cellular proteins, including the herpesvirus saimiri complement control protein homologue (CCPH), DAF, and MCP (Virgin et al., 1997). γHV68 ORF 4 includes four regions with homology to SCRs of RCA complement regulatory proteins. γHV68 gene 4, named γHV68 RCA, produces a 5.2 kb bicistronic mRNA of the late kinetic class, encoding multiple γHV68 RCA proteins, including both plasma membrane bound and soluble forms (Kapadia et al., 1999).

Functional studies indicate that γHV68 RCA interferes with both murine and human complement activation, resulting in a decrease in C3b deposition (Kapadia et al., 1999). γHV68 RCA was found to prevent activation of both the classical and alternative complement pathways (Kapadia et al., 1999).

The γHV68 RCA contributes to virulence in mice, as γHV68 virus mutated within the RCA protein was more attenuated during both acute and persistent γHV68 infection when compared with wild type or marker rescued virus (Kapadia et al., 2002). γHV68 RCA accomplishes this by interfering with the complement system, as the virulent phenotype of the γHV68 RCA protein mutant virus was restored in mice lacking C3. Interestingly, γHV68 RCA was not involved in evading C3 mediated innate immunity during latent infection.

Herpesvirus saimiri (HVS): complement control protein homologue (CCPH)

While determining the nucleotide sequence of genes within the vicinity of STP-A and STP-C (saimiri transformation associated protein of subgroup A and C), a gene was detected that encodes a protein displaying a significant degree of homology to the RCA protein family (Albrecht and Fleckenstein, 1992; Albrecht et al., 1992a). This protein, named complement control protein homologue (CCPH), is encoded by HVS 04, and contains four SCRs within its N-terminal domain (amino acids 21–265), seven potential amino-linked glycosylation sites, and a transmembrane domain.

HVS 04 was found to encode two transcripts, one full length, and one smaller, alternatively spliced form. The unspliced transcript encodes a membrane-bound glycoprotein (mCCPH) of 65–75 kD, similar to the membrane-bound RCAs MCP, DAF, CR1, and CR2. Splicing produced a secreted glycoprotein (sCCPH) of 47–53 kD, like the soluble complement inhibitors C4-binding protein and Factor H. Functional studies indicated a role for CCPH in complement regulation. Cells stably transfected with mCCPH were approximately two times more resistant to complement mediated cell lysis, with levels similar when compared with DAF as a control (Fodor et al., 1995).


In addition to HVS CCPH, sequence analyses of the HVS genome indicated the presence of a second gene, HVS 15 that encodes a protein sharing significant homology with the complement regulatory protein CD59 (Albrecht et al., 1992b). The HVS 15 ORF consists of 363 nucleotides, sharing 64% sequence identity with human CD59 cDNA and was predicted to encode a protein of 121 amino acids with 48% identity to human CD59. Both HVSCD59 and CD59 have hydrophobic carboxyl-terminal sequences, which for CD59, is replaced by a GPI anchor. Additional studies confirmed that HVS 15 protein product was also a GPI linked membrane glycoprotein (Rother et al., 1994). The overall structure of both HVS 15 and CD59 were expected to be very similar as the proteins shared amino acid identities and a single N-linked glycosylation site, and all cysteines were highly conserved.

Expression of either HVSCD59 or squirrel monkey CD59 (SMCD59), the natural host of HVS, on the surface of Balb/3T3 cells rendered the cells resistant to complement-mediated cell lysis by human serum (Rother et al., 1994). However, only HVSCD59 expressing cells were protected from challenge with rat serum, indicating that HVSCD59 is less species specific than either human or SMCD59. Protection occurred following C3b deposition, suggesting that HVSCD59 prevents complete formation and function of the membrane attack complex (Rother et al., 1994). It was hypothesized that the location of the N-linked glycosylation site was responsible for the less species restrictive phenotype of HVSCD59, as the N-linked glycosylation of human CD59 appears necessary for its function.

Viral proteins with no sequence homology, yet functional similarities with mammalian complement regulatory proteins, and that incorporate host complement regulatory proteins: PRV gC and unknown host cell derived complement regulatory protein(s)

Pseudorabies virus (PRV) is protected from complement-mediated innate immunity by the presence of at least two proteins able to interfere with complement, gC and one or more host cell derived complement regulatory proteins. PRV gC shares homology with gC from other members of the alpha-herpesvirus family, and like HSV-1 gC, mediates viral attachment and facilitates immune evasion by binding C3. Neutralization experiments comparing PRV-CPK, a virus containing both gC and host cell derived complement regulatory proteins, and PRV-ΔgC-CPK which expresses the host cell derived complement regulatory proteins, yet lacks gC were performed (Maeda et al., 2002). The PRV virus lacking gC was more readily neutralized by swine serum than the wild type virus, suggesting that gC protects PRV from complement-mediated neutralization.

Pseudorabies virus (PRV) in which gC was deleted was propagated on either swine kidney derived CPK or rabbit kidney derived RK13 cells and then tested for susceptibility to complement-mediated virus neutralization using either swine or rabbit serum as the source of complement (Maeda et al., 2002). Results indicated that the gC deletion mutant grown in the CPK porcine cells was protected from neutralization mediated by swine serum. However, PRV derived from the RK13 rabbit cells was susceptible, suggesting that in the absence of gC, PRV was protected by at least one additional complement regulatory protein. No known homologues of complement regulatory proteins exist within the PRV genome; therefore, a host cell derived complement regulatory protein likely confers protection. Additional studies indicated that while the greatest level of protection was obtained when both gC and the cell derived factor(s) were coexpressed, the cell derived factor(s) afforded the most protection.

Summary of viral complement regulatory proteins

The complement system is an early innate defense able to thwart viral infection. Viruses have evolved numerous mechanisms to interfere with complement that are summarized in Fig. 63.4. Strategies reflect those used by the host to regulate and control complement activation and include encoding complement regulatory proteins that can be secreted or expressed on the surface of virions and infected cells or up-regulating and incorporating the host’s own complement regulatory proteins on infected cells and within virions. Expression of complement control proteins by viruses can impart the capacity for increased infection and spread, resulting in greater virulence.


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