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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 31Human gammaherpesvirus immune evasion strategies

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Author Information

,1 ,2 and 3.

1 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
2 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
3 Division of Tumor Virology, New England Primate Research Center, Harvard Medical School, Southborough, MA, USA

Introduction

The human γ-HVs are able to establish a lifelong, persistent infection that is largely clinically inapparent within the immunocompetent host. However, when these viruses are not kept in check, a variety of lymphoproliferative and neoplastic disorders result that will be detailed elsewhere within this volume. In brief, for HHV-8, also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), these neoplasias include Kaposi’s sarcoma (KS), multicentric Castleman’s disease (MCD) and primary effusion lymphoma (PEL). HHV-4, or Epstein–Barr virus (EBV), has been etiologically associated with infectious mononucleosis, Burkitt’s lymphoma, nasopharyngeal carcinoma (NPC), Hodgkin’s disease, hemophagocytic lymphohistiocytosis syndrome and some gastric cancers. Through coevolution with their hosts, these viruses have acquired a number of genes that act to set a fine balance between the uncontrolled, virally driven cellular proliferation seen in the immunocompromised host and complete elimination of infected cells by the immune responses. Several of these gene products cause selective suppression of normal immune system functioning and allow for an apathogenic, persistent infection.

Immune system overview

The immune system provides multiple mechanisms of protection from invading pathogens, whether viral, bacterial or parasitic. These immune responses include both broad spectrum, innate responses and highly specific, adaptive responses. Mechanisms of the innate response include the production of viral replication blocking interferons, opsonization and lysis by the complement cascade and natural antibodies, apoptosis, as well as clearance of infection by natural killer (NK) cells, macrophages, neutrophils and T-cells. The adaptive response mechanisms include the CD4+ T-helper cell directed production of specific, high avidity neutralizing antibodies by the B-cells and elimination of infected cells by antigen-specific cytotoxic T-lymphocytes (CTL). A complex network of protein–protein interactions, providing numerous targets for viral intervention and deregulation, governs all of these processes.

Evasion of innate host immunity

By definition, the innate immune responses are the host’s first line of defense against viral infection. These defenses can be roughly broken down into complement-mediated responses (both antibody-dependent and -independent), cytokine responses, apoptotic responses and cell-mediated responses. These responses are broad, able to target multiple pathogens, but by no means non-specific. The innate immune response utilizes a large number of germ line-encoded receptors capable of sensing moieties that are common to many pathogens. Other members of the innate immune system, such as the natural killer (NK) cells, have evolved mechanisms for determining the “health” of a cell by examining the cell for changes in the repertoire of surface molecules. This complexity built in to the innate immune responses excludes the possibility of non-specific targeting of host cells, but also provides a number of regulatory checkpoints which invading pathogens can usurp. Both of the known human γ-HVs have devised a number of strategies for thwarting the efforts of the innate immune system to clear them from the body and for deregulating the cross-talk between the innate and adaptive responses.

Complement deregulation

The complement response is mediated by a series of heat-labile plasma proteins, each given a number designation, whose cleavage and activation from an inactive circulating zymogen is controlled by a host of regulatory proteins. It is initiated through one of three pathways: the classical, alternative or mannan-binding-lectin-associated serine protease (MASP) pathways (for review see Medzhitov and Janeway, 2000). Triggering of the complement response results in activation and cleavage of the first zymogen to its active form, which then in turn cleaves and activates the next zymogen in the cascade. After cleavage, the resulting zymogen products are given lettered subscripts. For example, the cleavage of the C4 zymogen by active C1 results in production of C4a and C4b products (Fig. 31.1). The complement system protects against infection by both bacteria and viruses in three different ways. First, several of the complement proteins, when activated, can covalently bind to pathogens in a process called opsonization. Complement receptor-bearing phagocytes can then internalize and clear the infecting organism. This opsonization also contributes to the activation of the adaptive, humoral response. Second, multiple complement protein cleavage products act as anaphylotoxins, recruiting and activating circulating phagocytes. Third, several activated complement proteins can form a large multimeric structure called the membrane attack complex (MAC). This protein complex is capable of creating a pore in lipid membranes resulting in the lysis of cells, enveloped virus or bacteria onto which it has been deposited. While each pathway is initiated by a different triggering event, they converge at the production of the multi-component C3 convertase and ultimately, each result to different degrees in opsonization, anaphylotoxin production and MAC formation. Regulation of the complement cascade is complex, involving proteins that mediate the degradation of complement components into inactive fragments, as well as other inhibitory proteins capable of irreversible binding to and inactivation of complement proteins. The γ-HVs have taken advantage of this complexity by encoding viral genes that interfere with this regulation which are outlined in Table 31.1.

Fig. 31.1. Outline of the Complement cascade with interfering herpesvirus products noted.

Fig. 31.1

Outline of the Complement cascade with interfering herpesvirus products noted. The complement cascade is a complex series of zymogens and regulating proteolytic enzymes. This high-level of complexity gives multiple opportunities for intervention by the (more...)

Table 31.1. Viral complement regulators. Complement forms an important facet of the innate immune response. Not only does it play a role in direct defense, through lysis of infected cells or enveloped viruses, but it also helps to co-ordinate later adaptive responses. Both human γ-herpesviruses encode gene products with the potential to alter the complement response. The open reading frame, product and potential function are listed for each, with additional details in the text.

Table 31.1

Viral complement regulators. Complement forms an important facet of the innate immune response. Not only does it play a role in direct defense, through lysis of infected cells or enveloped viruses, but it also helps to co-ordinate later adaptive responses. (more...)

KSHV encodes a homologue of the human complement control protein CD46 (Neipel et al., 1997a,b). Like its human homologue, the ORF4 gene product, termed KCP or Kaposica, contains four short consensus (SCR) or sushi domains. These domains are characteristic of the cellular regulators of complement activation (RCA) (Klickstein et al., 1987; Law, 1988). The SCR are typically 60–70 amino acids in length and contain four conserved cysteine residues, which are disulfide-linked. KCP/Kaposica is encoded from a 1650 nucleotide long open reading frame and work by Spiller et al. (2003) has demonstrated that it is expressed as three alternatively spliced constructs, an unspliced 550 residue form and two singly spliced forms of 425 residues and 347 residues (depicted in Fig. 31.2). All three forms retain the putative membrane-spanning region. The unspliced product (ORF4-F) has 14 N-X-S/T, consensus N-linked glycosylation sites. However, the NetNGlyc neural network N-linked glycosylation prediction program (http://www.cbs.dtu.dk/services/NetNGlyc) (Gupta et al. 2002), indicates that only 10 of these have a significant probability of being glycosylated. The other two forms, designated ORF4-M and ORF4-S, have five and four probable sites, respectively. Additionally, ORF4-F has potential for modification by O-linked glycosylation in a serine/threonine-rich region just upstream of the predicted transmembrane domain, while the other forms lack this region. Examination of the lysates of TPA-treated PEL cells showed three anti-ORF4 antibody reactive bands at 175 kD, 82 kD and 62 kD (Spiller et al., 2003). Examination of culture supernatants demonstrated the presence of only the two more slowly migrating forms. At this time, the contribution of glycosylation or additional post-translational modifications to the higher than predicted molecular weights of these products or differences in the functioning of each product has not been clarified. Since all of the proposed products maintain a trans-membrane domain, the mechanism of secretion also needs further investigation.

Fig. 31.2. Products of the Kaposica/KCP open reading frame.

Fig. 31.2

Products of the Kaposica/KCP open reading frame. The Kaposica/KCP open reading frame has multiple splice forms. Regions in bold are shared by all three isoforms. The underlined region is found in both the M and F forms. Green residues indicate the location (more...)

KCP/Kaposica strongly enhances the decay of the classical C3 convertase (C4b2a) but poorly promotes decay of the alternative pathway C3 convertase (C3bBbP) compared with the host complement control proteins (Mullick et al., 2003; Spiller et al., 2003). It acts as a co-factor to aid Factor I (fI), a major cellular complement control protein, in its degradation of both C4b and C3b (Fig. 31.1). Unlike cellular fI co-factors, however, KCP/Kaposica is able to drive production of the C3d complement protein as a final product of fI-mediated cleavage of iC3b (Spiller et al., 2003). Production of this molecule is usually driven by a cellular protease in a non-fi-dependent manner. In addition to accelerating decay of the C3 convertase, thus preventing the action of complement, this production of C3d by KCP/Kaposica probably plays an additional role in KSHV biology. The C3d molecule is capable of binding to complement receptor 2 (CR2, CD21), which complexes with CD19 and CD81, resulting in a dramatic increase in B cell responsiveness to B cell receptor stimulation (Dempsey et al., 1996). So, the actions of KCP/Kaposica likely have some effects on B cell production of antibodies in response to viral antigens. Whether this directly alters anti-viral responses or aids the virus in recruiting additional target cells or possibly altering viral entry is still unclear.

While no EBV-encoded proteins to date have been shown to have a direct effect on complement regulation, EBV also targets CR2. The gp350/220 viral envelope protein is capable of binding to and mediating viral entry into CD21+ cells. The binding of gp350/220 to CR2, while not identical to C3d, probably overlaps the complement binding region (Moore et al., 1991; Prota et al., 2002). However, it is currently unclear if binding to this receptor by EBV significantly alters complement activation or responses. Again, it is possible that the virus utilizes this ability to aid in dissemination without effects on complement. It is clear, however, that binding of EBV or the gp350/220 glycoprotein to CR2 has effects on cytokine production and survival for several cell types and will be discussed in later sections.

A number of other viruses have been shown to incorporate host complement regulatory proteins into their envelopes including human cytomegalovirus and HIV (Saifuddin et al., 1994; Spiller et al., 1996). While no experimental evidence has yet been shown for a similar strategy employed by the human γ-HVs, this is a tantalizing possibility.

Cytokine responses

The cytokines are a large number of mostly soluble proteins, able to bind to a wide variety of cellular receptors expressed both on other immune effectors and non-immune related host cells. Through binding to their receptors they can induce proliferation, differentiation and activation both in the producer cell (autocrine effects) and in other targets (paracrine effects). Included in this large group of proteins are several super-families of proteins including the interleukins, interferons and chemokines. Generally, the interleukins (usually given an IL designation) are proteins that are produced by one leukocyte and act on another, however numerous examples exist that don’t fall into this general definition. These proteins act to attract and activate a number of immune effector cells, activate the host acute-phase response and drive the differentiation of cells to result in a polarized immune response. The interferons (IFNs) are an evolutionarily conserved group of proteins that play a crucial role in the innate response to viruses. These proteins are able to mediate signaling through their receptors to induce the expression of a large number of cellular proteins that are able to alter cellular physiology to be less hospitable for viral replication. The chemokines interact with cellular 7-transmembrane, G-protein-coupled receptors (GPCRs) stimulating leukocyte trafficking and development, as well as regulating angiogenesis. Crucial to immune system functioning is their ability to recruit various effector cells to the site of inflammation. The spectrum of chemokines that are produced govern which cells respond to the site of inflammation and have a large influence in directing how the immune system reacts to invading pathogens. The signals that these cytokines transmit to the cells can stimulate the production of additional cytokines and chemokines, providing a complex cross-talk evolved to coordinate an effective immune response.

Two main subpopulations of CD4+ T lymphocytes, termed T helper (Th)1 and Th2 cells, coordinate the type of immune response that is made to an infecting pathogen. Th1 cells predominantly secrete IFN-γ, GM-CSF and TNF-α, but also secrete TNF-β, IL-3 and IL-2. Additionally, they usually express CD40 ligand and/or CD95 ligand on their surface. These types of cells act to activate macrophages, direct B-cells to produce opsonizing antibodies and cause inflammatory cell infiltration of tissues. Thus, the Th1 cells select for cell-mediated immune responses against pathogens. Th2 cells secrete IL-4 and IL-5, but also IL-10, TGF-β, eotaxin and IL-3. They also express CD40 on their surface. These types of cells act to activate antigen-specific B-cells to produce neutralizing antibodies and thus direct the immune effectors toward a humoral response against the invading pathogen. Additionally, the cytokines released by Th2 cells tend to inhibit inflammation. These two populations of T-lymphocytes result from the differentiation of naïve CD4+ T-cells in response to the cytokine milieu, cytokines which have been released from either infected cells or other immune effectors such as NK cells. Shifts in the dominance of Th1 or Th2 immune effectors can dramatically influence the type and importantly, the effectiveness of responses made against invading pathogens.

Interleukin and chemokine responses

KSHV expresses multiple chemokine homologues, homologues of the macrophage inflammatory proteins, vMIP-Ⅰ, -Ⅱ and –Ⅲ, a homologue of the cellular IL-6 protein and a homologue of the cellular Ox2 protein, which is involved in the release of a number of different cytokines. A summary of these gene products is outlined in Table 31.2. The viral MIPs are able to bind to a variety of cellular chemokine receptors, acting as agonist and antagonists (Boshoff et al., 1997; Kledal et al., 1997; Sozzani et al., 1998; Dairaghi et al., 1999; Endres et al., 1999; Stine et al., 2000). The gene products of ORFs K6 and K4 of KSHV, vMIP-I (vCCL1) and v-MIP-Ⅱ (vCCL2) respectively, share homology with the cellular CC chemokine macrophage inflammatory protein-1 alpha (MIP-1α) (Moore et al., 1996; Neipel et al., 1997a,b). The similar size of the K6 (95 residues) and K4 (94 residues) products and their high degree of sequence identity suggest that they arose through a gene duplication event. The third chemokine homologue, vMIP-Ⅲ (vBCK, vCCL3) is 114 residues in length, encoded by the K4.1 ORF and has homology with MIP-1β as well as several other members of the cellular CC chemokine family (Neipel et al., 1997a,b; Stine et al., 2000). The target of the vMIPs seems to be the Th2 lineage CD4+ T cells based on the fact that vMIP-I can act to induce chemotaxis of CCR8-bearing cells; vMIP-Ⅱ, chemotaxis of CCR3-bearing cells; vMIP-Ⅲ chemotaxis of CCR4 -bearing cells, and all of these receptors are found on Th2 cells (Sallusto et al., 1998) (Fig. 31.3). Each of the vMIPs have been shown to induce the chemotaxis of Th2 cells (Stine et al., 2000). Further, Weber et al. demonstrated that vMIP-Ⅱ is able to block the chemotaxtic effects of RANTES on Th1 cells and monocytes, thus inhibiting their recruitment to sites of vMIP production (Weber et al., 2001) (Fig. 31.3). Nakano et al. (2003), in contrast, demonstrated that vMIP-I and –Ⅱ induced chemotaxis of a monocyte cell line. However, these two groups used different experimental designs and much different target cells, a transformed monocyte cell line versus primary monocytes. The majority of the published data suggests that it is to the advantage of the virus to polarize the immune response to a Th2 pattern, suggesting that cellular adaptive immune responses are more likely to clear the virus from the body.

Table 31.2. Viral chemokine regulators. Recruitment of immune effectors is critical to the generation of an effective immune response. The soluble chemokines play a large role in this recruitment. Both human γ-herpesviruses encode multiple gene products with the potential to alter the chemokine response. The open reading frame, product and potential function are listed for each, with additional details in the text.

Table 31.2

Viral chemokine regulators. Recruitment of immune effectors is critical to the generation of an effective immune response. The soluble chemokines play a large role in this recruitment. Both human γ-herpesviruses encode multiple gene products with (more...)

Fig. 31.3. Herpesvirus skewing of the Th1/Th2 balance by multiple gene products.

Fig. 31.3

Herpesvirus skewing of the Th1/Th2 balance by multiple gene products. Both KSHV and EBV express multiple gene products that mimic cellular cytokines. These proteins have multiple effects on a number of immune effectors including the CD4+ T helper cells, (more...)

The vMIP proteins are also likely to have other effects in addition to their role in immune evasion. Both the vMIP-Ⅰ and –Ⅱ proteins are highly angiogenic in the chorioallantoic assay (Boshoff et al., 1997). Additionally, vMIP-1 can induce chemotaxis of endothelial cells through its interactions with the CCR8 receptor (Endres et al., 1999). Combined, this suggests that the vMIP proteins might be playing a large part in directing the development of the structure of the vascular KS lesions. Liu et al. (2001) have shown that addition of the vMIP-I protein to PEL cell lines resulted in the expression of vascular endothelial growth factor type A (VEGF-A). This VEGF-A can have both paracrine and autocrine effects, influencing PEL cell growth, extravasation and recruitment of other cells such as eosinophils, which can release Th2-type cytokines (Weber et al., 2001; Feistritzer et al., 2003) (Fig. 31.3). Again, pointing to a dual role for the vMIP proteins in directing KS lesion formation as well as altering anti-viral immune responses.

Further, supporting the thesis that KSHV better survives a Th2-biased immune response, the virus produces yet another soluble factor which favors the development of a Th2 response. Viral IL-6, encoded by KSHV ORF K2 is 204 residues in length and has approximately 25% homology with human IL-6 (Neipel et al., 1997a,b; Nicholas et al., 1997). Message for vIL-6 is very rapidly transcribed after infection (within 2 hours) and then is just as quickly downregulated, disappearing by 8 hours post-infection (Krishnan et al., 2004). Cellular IL-6 (cIL-6) performs multiple functions, including inducing the differentiation of B-cells into antibody-secreting plasma cells (Beagley et al., 1989). It promotes Th2 differentiation and simultaneously inhibits Th1 polarization through two independent molecular mechanisms. It also acts as both an autocrine and paracrine growth factor, delivering a signal through the IL-6 receptor, a heterodimer made up of gp80 and gp130 (Kawano et al., 1988; Klein et al., 1989; Kishimoto et al., 1995; Nakashima and Taga, 1998) (Fig. 31.3). This signal in many ways resembles the signal transmitted by INF-α/β interactions with its receptor, proceeding through members of the JAK kinase family to transmit a signal to the cellular STAT3, which can then stimulate transcription of a group of IL-6 responsive genes (Murakami et al., 1993; Narazaki et al., 1994; Stahl et al., 1994; Guschin et al., 1995). Additionally, STAT1 also becomes phosphorylated, dimerizing with STAT3 to bind and transactivate genes containing interferon-inducible GAS sequences (Feldman et al. 1994; Lutticken et al., 1994; Wegenka et al., 1994; Guschin et al., 1995). The stimulation of cells with cIL-6 also causes the phosphorylation of STAT5 and the induction of the MAP kinase pathway (Diehl and Rincon, 2002).

The KSHV vIL-6 protein, like cIL-6, has been shown to perform numerous functions. It is capable of activating STAT1, 3 and 5, as well as the MAP kinase signaling cascade (Molden et al., 1997; Osborne et al., 1999; Hideshima et al., 2000). However, unlike cIL-6, only the gp130 subunit of the IL-6 receptor is required, although the gp80 subunit can allow vIL-6 to signal more promiscuously (Molden et al., 1997; Aoki et al., 1999; Wan et al., 1999; Li et al., 2001; Klouche et al., 2002; Li and Nicholas, 2002). This ability to signal through the gp130 subunit alone probably allows vIL-6 to continue to transmit anti-apoptotic and growth stimulatory signals even after down regulation of the p80 protein, a normal cellular response to cIL-6 signaling. KSHV vIL-6 likely plays a critical role in the pathology of the virus. There are greater levels of expression in MCD and PEL samples than KS lesion samples, and one group has demonstrated high level vIL-6 production in KSHV-associated germinotropic lymphoproliferative disorder, a rare, newly described disease (Boshoff et al., 1996; Parravinci et al., 1997; Staskus et al., 1997; Du et al., 2002). Both cIL-6 and vIL-6 transmit a proliferative signal to PEL cell lines, both through induction of VEGF-B and induction of pro-survival pathways (Neipel et al., 1997a,b; Nicholas et al., 1997; Burger et al., 1998; Jones et al., 1999; Hideshima et al., 2000; Liu et al., 2001). Although there is great overlap in the functions of vIL-6, Foussat et al. demonstrated a clear need for cIL-6 in PEL cell tumor progression in mice (Foussat et al., 1999). Antibodies against cIL-6 slowed tumor growth even though vIL-6 was still being produced. In addition to a role of vIL-6 in delivering a positive growth signal and protecting from programmed cell death, it probably plays additional roles important to immune effector avoidance. As described above, cIL-6 is critical in driving immunoglobulin production from committed B-cells. The KSHV vIL-6 probably plays a similar role, further polarizing the immune responses, along with the other virally-encoded or –induced cytokines, toward a Th2 response. More recently, Klouche et al. demonstrated that unlike cIL-6, vIL-6 can induce the production of pentraxin-3 (PTX-3, TSG14) (Alles et al., 1994; Klouche et al., 2002). This acute-phase protein is capable of binding to apoptotic cells and preventing their recognition by dendritic cells, possibly preventing auto-immunity during the acute phase response in which there is a high amount of cell death (Rovere et al., 2000). Therefore, it is possible that the production of PTX-3 by vIL-6 helps to reduce recognition of virally-infected cells by APC. However, since PTX-3 only binds to C1q, the initiating protein of the classical complement pathway, or the surface of cells undergoing programmed cell death, the ability of vIL-6 to aid in immune avoidance through this mechanism requires additional experimental examination (Rovere et al., 2000; Mantovani et al., 2003; Nauta et al., 2003). Further underlining a potentially high importance of IL-6 to KSHV persistence or replication is the finding that the vFLIP protein, discussed later in detail, can induce the production of cIL-6 through interactions with TRAF2, which activates the JNK/AP1 pathway and induces IL-6 synthesis (An et al., 2003).

The cellular OX2 protein (CD200) plays a role in co-stimulation of activated T-cells and suppression of monocyte lineage cell responses (Borriello et al., 1997; Gorczynski et al., 1999). It has been shown to provide a co-stimulatory signal for activated T-cells, leading to an increase in IL-4 and TGF-β, but not IL-2 production (Borriello et al., 1997). In contrast OX2 delivers a negative signal to macrophage and monocytes, inhibiting their proliferation (Gorczynski et al., 1998; Gorczynski et al., 1999). Work by Foster-Cuevas et al. (2004) has shown that the interaction of OX2 with its receptor (CD200R) on activated macrophages results in a block to TNF-α production. In mice lacking OX2, dramatic increases in the macrophage and monocyte populations in the mesenteric lymph nodes supports the hypothesis that OX2 plays a role in negatively regulating these cell populations (Gorczynski et al., 1999).

KSHV encodes a gene product from ORF K14 with approximately 40% homology with human OX2. This viral protein is 271 residues in length, migrates with an apparent molecular weight of 55kDa and contains five putative N-linked glycosylation sites (Chung et al., 2002). The higher than predicted molecular weight and experiments with N-glycosidases suggest that all of the putative carbohydrate modification sites are used (Chung et al., 2002). The expression of vOX2 protein is increased after TPA-treatment of PEL cell lines. Although this homology is rather low it is still able to bind to CD200R with affinity and kinetics similar to OX2 (Foster-Cuevas et al., 2004). The biological activity of this viral OX2 is controversial. The experimental work of Chung et al. (2002) demonstrated that the viral protein, provided as a soluble GST-coupled protein, delivers a stimulatory signal to macrophage/monocyte and dendritic cells causing them to elicit several pro-inflamatory cytokines including interleukin-1β (IL-1β), IL-6, monocyte chemoattractant protein 1 (MCP-1), and TNF-alpha. Further, expression of vOX2 on the surface of a B-cell line could stimulate the production of TNF-α and IL-12 from U937 cells in the presence of IFN-γ. In contrast, Barclay’s group found that when vOX2 expressed on the surface of Chinese hamster ovary (CHO) cells was presented to human peripheral monocyte-derived macrophages there was no increase in TNF-α production (Foster-Cuevas et al., 2004). To the contrary, there was an inhibition of TNF-α production, similar to what was seen when cOX2 was delivered in a similar manner. Reductions were also seen in the amounts of MCP-1 and G-CSF. However, the experimental methodologies of these two groups were radically different. It is a distinct possibility that the two groups were measuring the effects of vOX2 on different receptors. Further experimental verification is still required to determine the biological activity of this protein. The exact role of this protein and the advantage it conveys upon this virus also still requires further study. One possibility is that the virus is altering the cytokine response profile to control or misdirect anti-viral immune effector proliferation and recruitment. Increases in IL-6 production would be expected to bias CD4+ Th2 cell generation. However, it is also possible that the virus is utilizing cellular cytokines to induce proliferation/recruitment of additional target cells as well as facilitating cytokine-mediated angiogenic proliferation to aid in viral dissemination. If vOX2 has a negative effect on monocyte stimulation it could be acting within KS lesions to block responses from the local infiltrating macrophages which could recruit other immune effectors.

EBV expresses a variety of genes that influence the cellular cytokine milieu. As mentioned previously, LMP-1 induces the expression of EBI-3 resulting in decrease in IL-12 production and increases in IL-27 secretion (Devergne et al., 1996, 1997). This has effects on IFN-γ and Th1 responses from both monocytes and CD4+ T cells (Nieuwenhuis et al., 2002; Pflanz et al., 2002) (Fig. 31.3). Further, the BCRF1 gene, a homologue of IL-10, also modulates cytokine production. Its expression limits the production of both IL-1 and IL-2 from CD4+ T-cells (de Waal Malefyt et al., 1991; Liu et al., 1997; Zeidler et al., 1997; Hayes et al., 1999). vIL-10 can also alter the responsiveness of dendritic cells to MIP-1α and MIP-1β. Although vIL-10 is expressed during the lytic program, LMP1 and the EBERs have been shown to induce production of cIL-10. Examination of immune responses against epitopes in LMP1 in EBV+ and EBV individuals demonstrated that the majority of responding cells were Th1 cells, which secrete IL-10, suppressing T-cell proliferation and IFN-γ production (Marshall et al., 2003) (Fig. 31.3). In addition to these specific genes that have been mentioned, EBV likely possesses a number of additional mechanisms for altering the host chemokine and cytokine profile. These changes seem to play a large role in driving the pathophysiology of EBV infection.

As is seen for KSHV, EBV seems to alter the cytokine milieu to favor the development of a Th2 response. The IL-12 protein influences naïve CD4 T-cells to differentiate toward a Th1 profile. EBI-3 decreases IL-12 production, thus reducing one pro-Th1 factor. Further cellular IL-10 can inhibit Th1 cell generation. The BCRF1 viral protein likely plays a similar role and additionally, like cellular IL-10, inhibits the Th1 cytokines IL-2 and IFN-γ. Again, further in vivo investigation is required to better understand the correlates of an effective immune response against the γ-HVs.

Interferon responses

The interferons (IFN) are a family of critically important cytokines that act to modulate cell proliferation and play an important role in innate and adaptive immunity. The type Ⅰ IFN-α/β and IFN-ω are produced by virally infected cells, whereas the type Ⅱ IFN-γ is produced by innate immune system effectors cells, as well as adaptive response effectors such as Th1 cells and CD8+ cells (Biron et al., 1999). These proteins act by binding a variety of cell surface receptors and transmitting a signal through the Janus protein kinases (JAKs) and signal transducers and activators of transcription (STATs) to induce expression of a variety of interferon response factors (IRFs) (reviewed in Leonard, 2001; Sato et al., 2001; Taniguchi et al., 2001). In turn, these IRFs regulate the transcription of a wide variety of genes containing either IFN-stimulated response elements (ISRE) or γ-interferon activation sequences (GAS) in their promoters. Regulated proteins include multiple protein kinases, the tumor necrosis factor receptor and MHC class Ⅰ and class Ⅱ proteins (Pober et al., 1983; Collins et al., 1984; Boehm et al., 1997; Stark et al., 1998). The interferon responsive proteins act to induce an anti-viral state in the expressing cells, targeting multiple steps in the life cycle of the virus. For example, through the action of the IFN-responsive oligoadenylate synthase, RNase L is activated. This endoribonuclease is active against double-stranded RNA (dsRNA), thus targeting those viruses with either dsRNA genomes, such as the Reoviridae (Miyamoto et al., 1983), or containing extensive dsRNA structure, such as the Picornaviridae (Robberson et al., 1982). Another major IFN-inducible gene is the protein kinase PKR, capable of phosphorylating the eIF-2α initiation factor, inhibiting mRNA translation and blocking the production of viral proteins (Thomis and Samuel, 1992). Yet a third major anti-viral interferon response is the induction of the MxA protein. MxA is a dynamin-like GTPase that is able to bind to the nucleocapsids of some viruses altering their intracellular transport (Haller and Kochs, 2002; Kochs et al., 2002). Further, the IFNs are able to stimulate the production of a number of other chemokines and cytokines, influencing the immune response to invading pathogens.

Activation of the IFN response can occur in at least two ways. First, as described above, binding of interferon to its cognate receptor on the surface of the cell transmits a signal that modulates the IRFs. However, this mechanism requires that IFNs already have been synthesized, either by the responding cell or a surrounding cell. Activation can also occur by a much more direct method. The cellular IRF-3 is part of a complex of proteins called the double-stranded RNA-activated transcription factor complex (DRAF1), which also includes p300/CREB binding protein (CBP) (Weaver et al., 1998). DRAF1 is sensitive to the presence of dsRNA and becomes serine/threonine phosphorylated upon viral infection. This results in a nuclear accumulation of DRAF1, where it binds to and activates ISRE sequences (Kumar et al., 2000). This results in the up regulation of a number of “interferon-responsive” genes as well as production of IFN-α and -β, which can then act in both autocrine and paracrine activation of the interferon pathway (Weaver et al., 1998). A schematic of the multiple mechanisms that the herpesviruses use to interfere with the IFN response pathway is given in Fig. 31.4 and detailed in the text below.

Fig. 31.4. Viral proteins involved in control of the anti-viral IFN responses.

Fig. 31.4

Viral proteins involved in control of the anti-viral IFN responses. A number of γ-HV proteins, detailed in the text and shown in a checkered pattern, are capable of interfering with the IFN responses. Some prevent STAT assembly on GAS, ISRE or (more...)

KSHV was the first virus identified as carrying an IRF (Moore et al., 1996). The K9 protein, vIRF-1, is a 449 residue product with some limited homology to the cellular IRFs (Moore et al., 1996). It is capable of inhibiting both type Ⅰ and Ⅱ interferon signaling and additionally has transforming activity (Gao et al., 1997; Li et al., 1997; Inagi et al., 1999) (Table 31.3). Expression in NIH 3T3 cells allows growth in soft agar and at low serum concentration (Gao et al., 1997). Further, these vIRF-1-expressing NIH 3T3 cells lose contact inhibition and are tumorigenic in nude mice. These activities of vIRF-1 are the result of interactions with multiple cellular proteins including the cellular IRF-1 and IRF-3 transcription factors, however it does not effect IRF-7-mediated transactivation (Lin et al., 2001). Interactions with these cellular IRFs block production of IFN-β and the RANTES chemokine, important in directing the infiltration of a number of leukocytes including NK and effector T-cells (Lin et al., 2001). These interactions also block the ability of IRF-1 and IRF-3 to direct transcription from the ISG and IFNA4 promoters. However, at least for IRF-3, binding by vIRF-1 did not effect dimerization, nuclear translocation and DNA binding activity. Rather, vIRF-1 interacted with the p300/CBP and efficiently inhibited the formation of transcriptionally competent IRF-3-CBP/p300 complexes (Lin et al., 2001). The further implications of the ability of vIRF-1 to interact with p300/CBP will be discussed later. Additionally, the interaction of vIRF-1 with the cellular IRF-1 is likely responsible for its ability to suppress CD95L up-regulation and FAS mediated cell death after TCR/CD3 stimulation (Kirchhoff et al., 2002). However, this effect might also be a result of interactions with p300/CBP. More recently, the group of Seo et al. (2002) identified an additional binding partner of vIRF-1, retinoid-IFN-induced-mortality-19 (GRIM19). This gene enhances caspase-9 activity and induces apoptosis in response to signals from IFN and retinoic acid treatment of cells. vIRF-1 binding suppresses the ability of GRIM19 to induce apoptosis in HELA and MCF-7 cells. This inhibition of apoptosis through interactions with multiple transcription factors along with an ability to increase c-myc expression all contribute to the transformation ability of vIRF-1.

Table 31.3. Viral interferon regulators. Both human γ-herpesviruses encode multiple gene products with the potential to alter the IFN response. The open reading frame, product and potential function are listed for each, with additional details in the text.

Table 31.3

Viral interferon regulators. Both human γ-herpesviruses encode multiple gene products with the potential to alter the IFN response. The open reading frame, product and potential function are listed for each, with additional details in the text. (more...)

KSHV encodes three additional vIRFs, vIRF-2, a 489 bp ORF encoded by the ORFK11.1 gene and its close homologue encoded by the ORFK11 gene and vIRF–3, also termed LANA-2, encoded as a 1072 bp spliced product of the ORF K10.5 and 10.6 genes (Burysek et al., 1999; Lubyova and Pitha, 2000). Over expression of these genes results in suppression of both IFN-α and -β signaling (Table 31.3). Unlike vIRF-1, the vIRF-2 protein does not seem to possess transforming activity (Burysek et al., 1999). It is capable of binding to several cellular factors including IRF-1, IRF-2, interferon consensus sequence binding protein, RelA/p65 and CBP (Burysek et al., 1999). vIRF-2 is capable of homodimerizing and binding to DNA encoding the NF-kB sequence (Burysek et al., 1999). More recently it was shown that vIRF-2 is able to interact with the double-stranded RNA-activated protein kinase (PKR) and prevent its autophosphorylation (Burysek and Pitha, 2001). As detailed above, PKR targets the elongation initiation factor 2α (eIF-2α), critical to the initiation of protein synthesis, phosphorylating the GDP-bound inactive form. This phosphorylated form acts as a dominant negative, binding to the eIF-2β guanine nucleotide release factor, preventing the reloading of GTP onto other eIF-2α molecules, thus preventing the initiation of new rounds of protein synthesis (Thomis and Samuel, 1992). All of these abilities of vIRF-2 contribute to its ability to block the effects of the Type Ⅰ interferons. Intriguingly, vIRF-2 transcripts are present at high levels within 2 hours of viral infection and then subside to undetectable levels by 8 hours post-infection (Krishnan et al., 2004). Further, like vIRF-1, vIRF-2 is able to block FAS-mediated apoptosis through an ability to block up regulation of CD95L on the surface of expressing cells (Kirchhoff et al., 2002).

The transcription pattern of vIRF-3 is more complicated than the other v-IRF genes. Its mRNA is a spliced product of two genomic regions previously thought to code for two separate proteins, ORF K10.6 and ORF K10.5 (Lubyova and Pitha, 2000). It has homology with the vIRF-2 and ORFK11 proteins as well as the cellular IRF-4 (Rivas et al., 2001). It can block the activities of both IRF-3 and IRF-7 on the IFNA promoter, inhibiting the production of both α- and β-interferon (Lubyova and Pitha, 2000). More recent work from Rivas and colleagues has shown that vIRF-3 is able to block PKR-mediated apoptosis, but not oligoadenylate pathway-mediated apoptosis (Esteban et al., 2003). In these studies the expression of vIRF-3 was able to prevent PKR mediated inhibition of protein synthesis, at least partially through a block to the phosphorylation of eIF-2α. Further, vIRF-3 was able to block the activation of caspase 3, a member of the FADD/caspase 8 pathway of apoptosis that is activated by PKR. However, no effects of vIRF-3 were observed on caspase 9, another PKR activated caspase. Since vIRF-2 also targets the PKR pathway, an exploration of the co-expression of these genes and their potentially additive effects on antiviral interferon responses would be interesting.

More recently, in a comprehensive screen of the KSHV lytic genes, Ganem’s group identified a viral protein capable of blocking interferon signaling at a membrane proximal position, unlike the majority of KSHV gene products that block responses in the nucleus. ORF 10, now named RIF (regulator of Interferon Function), is able to block phosphorylation of STAT1, STAT2 and Tyk2 following IFN-α stimulation (A-L Page, SA Bisson and D Ganem, personal communication). Interestingly, this viral protein directly interacts with the STAT proteins, potentially blocking their multimerization. This mechanism seems distinct from that of the EBV BZLF1 gene product ZTA, which will be discussed in detail later in this section, as ZTA only blocks STAT1 phosphorylation following IFN-γ stimulation, not IFN-α (Morrison et al., 2001).

The interferon responses typically take place very quickly after viral infection. Therefore, in order to persist within the host the virus must take immediate protective action. Zhu et al. have identified a KSHV protein encoded by ORF45 that is incorporated into the virus particle as a tegument protein (Zhu and Yuan, 2003). This protein, KIE-2, is able to bind to IRF-7, blocking its phosphorylation and accumulation in the nucleus (Zhu et al., 2002). This results in a blockage of IFN-α and IFN-β transcription in response to viral infection. As its name suggests, KIE-2 is an immediate early protein of ∼78kDa and is found within the cytoplasm of expressing cells. Based on the presence of the protein in preparations of purified virus and its resistance to detergent treatment combined with sensitivity to detergent plus trypsin suggests that this protein is found in the tegument of the virus. This protein, therefore, would be available to block the interferon responses immediately following viral infection.

KSHV possess yet an additional way of mitigating the effects of interferon on viral replication and persistence. The viral IL6 homologue is able to block the induction of p21CIP1/WAF1, a cyclin-dependant kinase inhibitor, by IFN-α (Table 31.3). Normally treatment of cells results in an up regulation of this protein, arresting the cells in G1/S (Chatterjee et al., 2002). Further, treatment of cells with vIL-6 was shown to block the IFN-α stimulated binding of ISGF3 to ISRE probes. Interestingly, IFN-α downregulates the gp80 sub-unit of the IL-6 receptor blocking the ability of cIL-6 to transmit a signal. On the other hand, vIL-6 only requires the gp130 sub-unit to signal and thus, is not blocked by the down regulation of gp80. Additionally, vIL-6 expression is induced by IFN-α, providing a negative feedback loop to control this antiviral response in virally-infected cells.

One remaining question is why seven different gene products potentially involved in regulating the cellular IFN responses are encoded by the virus. Several non-exclusive answers exist. First, although each of the studied products possess similar functions, they are not identical. Given the importance of the IFN response in the control of other viruses, as well as a proven ability of interferon treatment to block KS progression in a large percentage of patients, this simplistic answer is probably also true (Von Roenn and Cianfrocca, 2001). Recent work by a number of groups using DNA array technology has pointed to another potential answer. When examining expression of each vIRF gene, it was found that the kinetics and tissue-expression of each differed (Jenner et al., 2001; Paulose-Murphy et al., 2001; Fakhari and Dittmer, 2002; Dittmer, 2003). Unlike vIRF-1, the vIRF-3/LANA-2 protein is detectable in primary effusion lymphoma (PEL) cell lines without TPA stimulation. The work of Fakhari and Dittmer demonstrated that the kinetics of vIRF-3/LANA-2 mRNA production mirrored that of LANA-1, v-FLIP and v-cyclin, all non-TPA induced, latency-associated genes in the BCBL-1 PEL cell line (Fakhari and Dittmer, 2002). In KS lesions, however, expression of vIRF-1 and not vIRF-3 clusters with LANA-1. So, a degree of tissue- or disease-specific expression might also contribute to the need for multiple genes to combat this facet of innate immunity. An understanding of the role of the vIRFs during infection is further complicated by the work of Pozharskaya et al. (2004). In experiments looking at vIRF-1 it was found that during latency in BCBL-1 PEL cells, only low levels of vIRF-1 are expressed and are not able to block the effects of IFN-α and while higher levels were initially expressed after TPA induction, these levels quickly fell off. Further, the vIL-6 gene is transcribed to high levels shortly after infection (Krishnan et al., 2004). In summary, KSHV expresses multiple genes capable of blunting the production and effects of the interferon genes. These genes are expressed during both the lytic and latent programs, underlining the importance of the interferon proteins in the control of viral infection.

Like KSHV, EBV encodes multiple genes that help it avoid the antiviral effects of interferon. Among these are BCRF1, BZLF1 and BARF1 (Table 31.3). Additionally, viral infection induces the expression of a cellular protein named EBI-3, also involved in regulating the effects of interferon. The mature BCRF1 gene product (vIL-10) possesses 84% identity with cellular interleukin-10 (Hsu et al., 1990). A 170 residue protein, it is expressed late in the lytic program, although one group reports expression of BCRF1 in a small number of patients with nasal type, extranodal natural killer (T(NK/T)-cell) lymphoma, which is usually associated with latent EBV infection (Swaminathan et al., 1993; Xu et al., 2001). This gene product indirectly effects the production of the type Ⅱ IFN-γ by binding to the cellular IL-10 receptor. This results in a blockage of IL-2 and IFN-γ production (Liu et al., 1997; Takayama et al., 2001). Like cellular IL-10, vIL-10 can block the maturation of dendritic cells causing them to down regulate CCR7 and up regulate CCR5. This blunts their ability to stimulate T cell release of IFN-γ (Takayama et al., 2001). In addition to aiding the virus in escape from IFN responses this has profound effects on CTL induction, which will be discussed in a later section of this chapter. Viruses containing a truncated BCRF1 protein or completely deleted for the gene were functionally similar to wild-type virus (Swaminathan et al., 1993). Like the parental virus, BCRF1 deleted virus was able to transform B-lymphocytes into long-term lymphoblastoid cell lines (LCLs), and these LCLs were capable of inducing tumors in SCID mice to the same degree as wild-type derived LCLs (Swaminathan et al., 1993). This suggests that BCRF1 is playing a larger role in immune regulation than in viral pathogenesis.

The BZLF1 gene expresses an immediate early viral protein with a wide number of functions. Not only is it important in directing the lytic replication program through its binding to the lytic origin of replication and within several of the early lytic gene promoters, but it also blocks tyrosine phosphorylation and nuclear translocation of STAT1, an important molecule in IFN response signaling (Kenney et al., 1989; Rooney et al., 1989; Packham et al., 1990; Morrison et al., 2001). Additionally, this protein blocks IRF-1 activation and decreases the amount of IFN-γ α-chain receptor expression (Morrison et al., 2001). BZLF1 is able to decrease the ability of IFN-γ to activate a variety of important downstream target genes, such as IRF-1, p48, and CIITA, and prevents IFN-γ-induced class Ⅱ MHC surface expression (Morrison et al., 2001). Like BCRF1, not only does BZLF1 affect interferon responses, but it also interferes with activation of helper T-cells and it possesses anti-apoptosis activity, both of which will be discussed in greater detail in later sections of this chapter. Interestingly, through competition for limiting amounts of the SUMO-1 protein, BZLF1 can also disperse nuclear PML bodies, which are induced by interferon and posited to have antiviral effects (Adamson and Kenney, 2001).

The BARF1 gene encodes a 31–33 kDa soluble receptor for colony stimulating factor 1 (CSF-1) that is expressed as an early lytic gene (Wei and Ooka, 1989; Strockbine et al., 1998). Its expression inhibits macrophage proliferation and blocks IFN-α production by monocytes (Cohen and Lekstrom, 1999). Additionally, BARF1 can act as an oncogene when expressed in fibroblasts, B-lymphoma cells and monkey kidney cells (Wei and Ooka, 1989; Wei et al., 1994, 1997). It increases c-myc, CD21 and CD23 expression and introduction into EBV Akata cells resulted in increased Bcl-2 expression and tumor induction in SCID mice (Wei et al., 1994; Sheng et al., 2001, 2003). However, Cohen and Lekstrom (1992) demonstrated that a BARF1 virus was competent for B cell transformation. Groups have reported that in both gastric adenocarcinomas and NPC, BARF1 is strongly expressed along with a number of the other latent proteins (Hayes et al., 1999; Decaussin et al., 2000; zur Hausen et al., 2000). In the case of EBV positive gastric adenocarcinomas, this is in the absence of the LMP1 oncogene, giving greater weight to the ability of BARF1 to act as an oncogene, at least in certain tissues or cell-types. Fewer reports have been made concerning the potential immune evasion role of BARF1.

One final gene utilized by EBV to control the anti-viral interferon responses is encoded by the host and induced by the LMP1 protein (Devergne et al., 1996, 1998). EBV-induced gene-3 (EBI-3) is a 34 kDa glycoprotein which localizes primarily to the ER of expressing cells (Devergne et al., 1996). It is homologous to the IL-12 p40 subunit and can bind to IL-12 p35 (Devergne et al., 1996). IL-12 normally triggers Th1 polarization of naïve CD4+ T-cells, which then secrete IFN-γ. Recently, Pflanz and coworkers (Pflanz et al., 2002) demonstrated that IL-27 is made up of a complex of EBI-3 and IL-12 p35. This interleukin is produced by activated antigen presenting cells and can drive expansion of naïve CD4+ T cells, although the effects on EBV are not yet clear since IL-12 can synergize with IL-27 for IFN-γ production and effect both CTL and NK cell development (Pflanz et al., 2002). An EBI-3-knockout mouse has normal numbers of most immune effectors except invariant natural killer T cells. This results in decreased IL-4 production and some decreases in IFN-γ production. The cellular EBI-3 protein, therefore, is playing a critical role in the generation of Th2 immune responses and its induction by EBV infection probably drives polarization of the anti-viral immune response (Nieuwenhuis et al., 2002).

The LMP1 protein makes at least one potential additional contribution to viral avoidance of the interferon defenses. Quizzically, LMP1 induces the expression, activation and nuclear translocation of IRF-7, the same IRF that the KSHV ORF45 gene product inactivates (Zhang and Pagano, 2001; Zhang et al., 2001). It has been shown that expression of LMP-1 in cells induces a number of ISGs and can block the replication of vesicular stomatitis virus (Zhang et al., 2004). The paradoxical stimulation of what would seem to be an antiviral state within the cell most likely plays a role in controlling EBV latency and superinfection of EBV+ cells by other viruses.

Thus, like KSHV, EBV encodes numerous proteins capable of altering the antiviral interferon responses. These proteins are expressed at multiple time points during the viral life cycle, highlighting how important the interferon responses are for the control of viral infections. Further examination of these groups of genes in an in vivo context should yield important information about how the interferon responses are modulated within the host.

Apoptosis responses

Apoptosis or programmed cell death plays a role both in innate immunity and normal cellular regulation. It is a mechanism by which intrinsic or extrinsic signals are capable of inducing cell death for the purposes of removing a diseased or unwanted cell from the body. Central to the intrinsic apoptotic responses are the members of the BCL-2 protein family. These proteins are capable of either inducing or suppressing apoptosis and possibly function through homo- or hetero-dimerizing with other family members, although this is controversial. The extrinsic responses, such as those triggered by CD8+ CTL, largely depend on members of the tumor necrosis factor (TNF) receptor family. These receptors contain death response domains in their cytoplasmic tails and upon multimerization transmit a signal to the intracellular caspases that initiate the apoptosis response. It is critical that the γ-HV control apoptosis in order to insure that the infected cell is not eliminated prior to virion production.

Both EBV and KSHV encode homologues of the cellular Bcl-2 gene (Table 31.4). The KSHV Bcl-2 homologue (vBcl-2) is expressed from ORF16, but only possesses low homology with cellular Bcl-2 (Russo et al., 1996; Neipel et al., 1997a,b). Little is known of the mechanism of action of this protein. While it can inhibit Bax toxicity in yeast and fibroblasts, there is conflicting data concerning its ability to dimerize with the cellular Bcl-2 family members (Cheng et al., 1997; Sarid et al., 1997). Additionally, vBcl-2 is capable of blocking the apoptosis induced by viral cyclin, so whether KSHV vBcl-2 is acting to protect virally infected cells against the extrinsic pro-apoptotic immune responses or intrinsic virally-mediated apoptotic responses is unclear (Ojala et al., 1999, 2000).

Table 31.4. Viral apoptosis regulators. Cellular suicide, whether self-induced or induced by other effectors, is an important immune response to control the replication and spread of viruses. Both human γ-herpesviruses encode multiple gene products with the potential to alter the cell suicide, apoptosis response. The open reading frame, product and potential function are listed for each, with additional details in the text.

Table 31.4

Viral apoptosis regulators. Cellular suicide, whether self-induced or induced by other effectors, is an important immune response to control the replication and spread of viruses. Both human γ-herpesviruses encode multiple gene products with the (more...)

In addition to a Bcl-2 homologue, KSHV also encodes a homologue of the cellular FLICE inhibitory protein, termed vFLIP (Chang et al., 1994). It is expressed from ORF13 as a multi-cistronic transcript with ORF72 (vCyclin) and ORF73 (LANA) through either differential splicing or expression from an IRES element (Sarid et al., 1999; Grundhoff and Ganem, 2001; Low et al., 2001). FLICE, or caspase-8, is a member of the ICE family of cellular caspases, and is important in the apoptosis response (Muzio et al., 1996). Interestingly, all three of these genes are transcribed rapidly after infection, underscoring a potential need to combat the apoptotic response soon after viral entry into cells (Krishnan et al., 2004). The vFLIP protein has been shown to block pro-apoptotic signaling mediated by the Fas-receptor, resulting in decreases in caspase-8, -9 and –3 activity (Thome et al., 1997; Djerbi et al., 1999; Belanger et al., 2001). A recent study has shown that vFLIP can target the NF-kB pathway, up regulating Bcl-x(L) resulting in protection of cells from serum withdrawal (Sun et al., 2003). Additionally, vFLIP physically interacts with tumor necrosis factor receptor associated factor 2 (TRAF2) activating the JNK/AP1 pathway in a TRAF-dependent fashion (An et al., 2003). This modulation of the JNK/AP1 pathway results in the induction of IL-6, important in directing a Th2 polarization of the immune response and having proliferative effects as detailed earlier (An et al., 2003). Further, vFLIP expression promoted tumor formation after injection of syngeneic and semiallogeneic mouse strains with A20 cells expressing this protein (Djerbi et al., 1999).

The K9/vIRF-1 protein, able to block the anti-viral interferon responses as described above, also has a role in blocking programmed cell death. In addition to binding cellular IRF and GRIM19, vIRF-1 has been shown to bind both p53 and p300/CBP through tryptophan- and proline-rich sequences (Li et al., 2000; Seo et al., 2000; Nakamura et al., 2001; Seo et al., 2001). The irreversible cell cycle arrest and cell death induced by p53 are considered part of host surveillance mechanisms for detecting and preventing viral infection and tumor induction. The activity of p53 is regulated by a series of kinases, phosphatases and acetylases. Acetylation of the carboxyl-terminal region of p53 is mediated by p300 and p300/CBP-associated factor (PCAF) (Sakaguchi et al., 1998). This modification leads to increased DNA binding activity. Interactions of vIRF-1 with p53 and p300/CBP lead to decreased acetylation of p53 as well as decreased phosphorylation, resulting in a dramatic decrease in p53 activity (Nakamura et al., 2001). Blocking p53-dependent transcription suppresses Bax and p21 transcription, mediators of p53-mediated apoptosis, thus rescuing vIRF-1 expressing cells from programmed cell death (Nakamura et al., 2001; Seo et al., 2001). Additionally, interactions of vIRF-1 with CBP results in hypoacetylation of histones H3 and H4, reducing transcription from the early inflammatory gene promoter (Li et al., 1998).

KSHV encodes at least one additional protein that has anti-apoptotic activity. The K7 protein, also termed vIAP, localizes to the mitochondria of expressing cells where it can interact with the cellular calcium-modulating cyclophilin ligand (CAML) (Feng et al., 2002; Wang et al., 2002). This interaction helps to maintain the mitochondrial membrane potential after treatment with a variety of pro-apoptotic compounds including TRAIL, staurosporin and thapsigargin (Feng et al., 2002). Additionally, K7 has been shown to interact with the Protein-linking integrin-associated protein and cytoskeleton 1 (PLIC1) (Feng et al., 2004). PLIC1 is capable of dimerizing and binding to poly-ubiquitin containing proteins, as well as associating with the 19s unit of the proteasome (Feng et al., 2004). KSHV K7 is able to reduce the ability of PLIC1 to homodimerize and bind to ubiquitinylated proteins, with the end result that two of the targets of PLIC1 activity, Iκb and p53, are rapidly degraded in the presence of K7 (Feng et al., 2004). This reduction of p53 levels within the cell contributes to the anti-apoptotic action of K7. Finally, the K7 protein has also been shown to interact with cellular Bcl-2 and caspase-3, but not with Bax and these interactions are critical to its anti-apoptotic activity (Wang et al., 2002). Like the vFlip gene, K7 is transcribed rapidly after viral infection (Krishnan et al., 2004).

The EBV BHRF1 protein is an early lytic protein capable of blocking the pro-apoptotic actions of TNF-related apoptosis inducing ligand (TRAIL) and FAS (Cheng et al., 1997; Foghsgaard and Jaattela, 1997; Kawanishi, 1997; Kawanishi et al., 2002). TRAIL normally causes cleavage of Bid, a BCL-2 family member, via activation of caspase 8. BHRF1 doesn’t block Bid cleavage, but it does block loss of mitochondrial membrane potential, an important downstream apoptotic effect (Kawanishi et al., 2002). Recently, the NMR structure of BHRF1 was solved, demonstrating some clear differences with the structure of its cellular counter-part (Huang et al., 2003). Unlike Bcl-2, it does not contain a hydrophobic groove important in homo- or hetero-dimerization with other apoptotic factors. Additionally, BHRF1 doesn’t bind to peptides from Bak, Bax, Bik, and Bad, indicating it functions in a fundamentally different way than the cellular Bcl-x(L) or Bcl-2 (Kawanishi et al., 2002; Huang et al., 2003). BCRF1 protein is also able to complex with another EBV protein, EBV nuclear antigen leader protein (EBNA-LP) (Matsuda et al., 2003). Previously it was shown that EBNA-LP can bind to the HS1-associated protein X-1 (HAX-1), while more recently it was shown that this protein can bind to cellular Bcl-2 (Kawaguchi et al., 2000; Matsuda et al., 2003). The implications of this complex web of interactions to apoptosis is made more complicated by a third EBV protein, BALF1. BALF1 is also an early lytic, Bcl-2 homologue (Hatfull et al., 1988). It can interact with both the Bak and Bax BCL-2 family members and was originally demonstrated to have apoptotic effects (Marshall et al., 1999). More recent experiments have shown that BALF1 can block the action of BHRF1 through an unknown mechanism, but itself has no direct pro- or anti-apoptotic activity (Bellows et al., 2002).

The LMP-1 gene of EBV is expressed during latency and has been shown, in addition to its latency regulatory activity, to prevent apoptosis. It can increase the expression of cellular Bcl-2 as well as a number of other cellular proteins including A20 and TRAF1, important in the anti-apoptotic TNF receptor pathway, through its activation of NF-κB (Henderson et al., 1991; Devergne et al., 1998). LMP-1 is additionally able to induce the expression of bfl-1, a Bcl-2 homologue able to suppress p53 mediated apoptosis (D’Souza et al., 2000). Ectopic expression of bfl-1 in an EBV-positive cell line exhibiting a latency type Ⅰ infection protects against apoptosis induced by growth factor deprivation, thereby providing a functional role for bfl-1 in this cellular context and adding bfl-1 to the list of anti-apoptotic proteins whose expression is modulated by EBV.

As outlined in this section, the γ-HVs encode a large number of proteins aimed at controlling the cellular apoptosis response. These proteins likely aid the virus in escape from immune effectors such as NK cells and CTL, as well as preventing viral replication from inducing cell death. Given the central importance of programmed cell death in immune function, additional viral mechanisms to avoid apoptosis are likely to be discovered.

Natural killer (NK) cell responses

The NK cells play a critical role in clearing virally-infected cells through direct lysis and the release of various cytokines, which coordinate other immune responses. Although the task that they perform is simple, their regulation is not. A complex set of cell:cell interactions determine whether the NK cell will release its deadly cargo of perforin and granzyme to induce programmed cell death in the target cell, secrete large amounts of IFN-γ to stimulate Th1 T cell production or release the target cell unharmed. The cell surface receptors that govern NK activity can be split into four classes (for review see Anderson et al., 2001; Boyington et al., 2001; LaBonte et al., 2001; Long et al., 2001; McVicar and Burshtyn, 2001; Volz et al., 2001). The killer cell immunoglobulin receptors (KIR) make up the first class. They are capable of binding to a variety of MHC class Ⅰ haplotypes and generally transmit a negative signal. The second class is the C-type lectin receptor family composed of heterodimers of CD94 and one of several NKG2 proteins. Like the KIR, these receptors also bind MHC class Ⅰ molecules, but only HLA-G and –E. The natural cytotoxicity receptors (NCR) compose the third class of receptors. The NCR don’t interact with class Ⅰ, but as of yet no cognate ligands have been identified. All identified NCR transmit positive signals to their expressing NK cells, inducing killing and cytokine release in the absence of stronger negative signals. The fourth class, the leukocyte immunoglobulin-like receptor (LIR) family, similar to the class two receptors, can bind HLA-G to transmit a negative signal. The net overall strength of each positive and negative signal determine whether the NK cell will be turned on to make a response or induced to release the target cell.

Important to NK surveillance are multiple adhesion molecules on both the NK and target cell. These molecules include the integrins, intracellular adhesion molecule 1 (ICAM-1), CD2 and LFA3. Interactions between these molecules help to bring the NK cell into close conjugation with its target. This allows both for the NK cell to survey the target cell for the many positive and negative regulatory factors and to potentially deliver the perforin/granzyme payload specifically to the closely juxtaposed target. Antibodies that block the binding of the NK adhesion molecules to the target cell have been shown to block NK cell lysis (Papa et al., 1994; Komatsu and Kajiwara, 1998). Experiments from Burshtyn et al. demonstrated that when the KIR interacts with MHC class Ⅰ on the target cell and transmits a negative signal, there is a decrease in the ability of the NK cell to stay in conjugation with the target (Burshtyn et al., 2000).

The KSHV K5 protein is capable of inducing the down regulation of several cell surface proteins through increasing their rate of endocytosis. This protein will be further discussed later, but as a brief introduction, K5 seems to act as an E3 ubiquitin ligase, targeting ICAM-1, B7.2 and some MHC class Ⅰ haplotypes for destruction by the ubiquitin: proteasome system (Coscoy and Ganem, 2000; Ishido et al., 2000a,b; Coscoy and Ganem, 2001; Coscoy et al., 2001; Means et al., 2002; Sanchez et al., 2002). This destruction happens in a sequential manner with the targeted proteins first being endocytosed from the cell surface into the trans-Golgi network (Means et al., 2002). Target proteins are then redirected into the lysosome, where they undergo destruction (Means et al., 2002). While MHC Ⅰ normally acts to transmit a negative signal to NK cells, the ICAM-1 and B7.2 molecules act as anchors to bring the NK cell into close conjugation with target cells. By removing these last two molecules from the surface of infected cells, K5 reduces the average time that the NK cell stays in contact with the K5-expressing target cell (Table 31.5). Thus, even without MHC class Ⅰ present to transmit a negative signal through the KIR, the NK cell releases the K5-expressing cell unharmed, simply because it can’t stay in contact long enough to get a strong positive signal and turn on granzyme/perforin or cytokine release (Ishido et al., 2000a,b) (Fig 31.5).

Table 31.5. Viral NK regulators. The immune system employs a number of specialized cellular effectors that perform general “house-keeping” function, including the elimination of diseased cells. The natural killer cells are a sub-set of these effectors that are capable of sensing the health of a cell through a number of cell surface receptors, including several which recognize MHC class Ⅰ. Both human γ-herpesviruses encode gene products with the potential to alter the response of NK cells to infection. The open reading frame, product and potential function are listed for each, with additional details in the text.

Table 31.5

Viral NK regulators. The immune system employs a number of specialized cellular effectors that perform general “house-keeping” function, including the elimination of diseased cells. The natural killer cells are a sub-set of these effectors (more...)

Fig. 31.5. Viral alteration of immunomodulatory proteins.

Fig. 31.5

Viral alteration of immunomodulatory proteins. Through the down regulation of multiple immunomodulatory proteins both KSHV and EBV are able to alter the ability of innate and adaptive immune effectors to recognize and mount responses against virally infected (more...)

Less information is available concerning the avoidance of NK cell responses by EBV. The work of Devergne et al. (2001) demonstrated that the EBV-induced EBI-3 protein is capable of stabilizing HLA-G presentation on the surface of cells (Table 31.5). HLA-G1 is capable of transmitting a negative signal to NK cells, preventing the activation of killing or cytokine elicitation (Adrian Cabestre et al., 1999; Navarro et al., 1999; Rajagopalan and Long, 1999). Further, HLA-G1 expression was shown to block the lysis of cells presenting HLA-A2-restricted influenza epitopes to specific CTL clones (Le Gal et al., 1999). However, no experimental data has been presented to demonstrate that the LMP1-mediated up regulation of EBI-3 is able to convey these immune avoidance phenotypes in the context of EBV infection (Fig 31.5). One other mechanism that EBV may be using to avoid NK surveillance is through direct infection. While NK cells lack the CD21/CR2 EBV receptor, studies have shown that they become briefly CD21+ after conjugation with CD21+ B-cell targets (Tabiasco et al., 2003). Acquisition of this molecule allows for EBV infection and likely underlies the genesis of EBV+ NK cell lymphomas, while at the same time allowing for viral escape from NK surveillance.

While it is clear that both of the human γ-HV interfere with NK cell surveillance the possibility of additional viral mechanisms for avoiding these effectors remains. For example, the human cytomegalovirus (HCMV), a β-herpesvirus, encodes the UL16 protein. This protein is able to bind and down regulate the cellular UL16-binding proteins (ULBP) 1 and 2, which are ligands for the c-type lectin NKG2D activating receptor on NK cells (Rolle et al., 2003). This effectively protects HCMV-infected cells from NK cell lysis. To date, no human γ-HV protein has been shown to target an NK cell activating receptor.

Evasion of other innate cellular responses

The immune system employs a number of additional innate effectors which surveil the body, including the professional phagocytes, neutrophils and macrophage that internalize and destroy extracellular pathogens such as bacteria or virus, as well as eosinophils and basophils, both able to release a number of immunomodulatory proteins. Like NK cells, these cells represent the first line of defense against infecting pathogens and are able to modulate the later adaptive responses. It is therefore critical that the γ-HV deregulate or avoid recognition by these cells in order to establish a persistent infection.

EBV is able to infect both neutrophils and monocytes, macrophage-precursors. While EBV infection of neutrophils is abortive, multiple changes in cellular physiology important to the potential escape of the virus from immune avoidance occur (Larochelle et al., 1998). First, viral infection causes the up regulation of Fas ligand. Neutrophils express CD95/Fas, which plays a role in immune privilege, and the increased expression of Fas ligand results in apoptosis (Griffith et al., 1995; Larochelle et al., 1998). This effectively eliminates responding neutrophils. However, EBV infection also triggers these cells to release a number of cytokines, including IL-8, MIP-1α, IL-1α, IL-1β and the IL-1R antagonist (Beaulieu et al., 1995; McColl et al., 1997; Roberge et al., 1997). These chemokines, along with the highly-induced leukotrien B4, act to recruit additional leukocytes, potentially aiding in viral dissemination (Gosselin et al., 2001).

In contrast, infection of monocytes, while highly inefficient, seems to be productive, resulting in transformed monocyte cell lines displaying type Ⅱ latency (Masy et al., 2002). The route of infection is unclear since monocytes do not express detectable levels of CD21, however, transient CD21 expression might result from the engulfment of CD21+ cells (Inghirami et al., 1988). Addition of the gp350/220 glycoprotein of EBV to monocytes results in the elicitation of IL-1, IL-6 and TNF-α (D’Addario et al., 1999; 2000). However, addition of the whole virus does not up regulate IL-1 expression and blocks TNF-α secretion (D’Addario, 1999; Gosselin et al., 2001). Finally, EBV infection has been shown to decrease the production of prostaglandin E2 (Savard et al., 2000). This would be expected to induce or favor a Th1 response, but in the face of other virally-elicited cytokines, it probably acts to elicit an inflammatory response, recruiting additional targets for viral infection.

These alterations in innate cellular responses along with the alterations in eosinophils function described earlier likely all contribute to long-term control of the anti-viral immune responses. By controlling the cells which initially determine the direction the immune response is to take, the γ-HV are able to insure that they are able to establish a persistent infection. Using these cells, the virus is able to skew responses made by the immune effectors such that the additional immunomodulatory genes are most effective.

Evasion of adaptive host immunity

The adaptive immune responses are mediated by the CD4+ and CD8+ T-cells and the antibody producing B-cells. Like the innate responses, there are multiple levels of regulation and therefore, multiple opportunities for viral intervention. The adaptive immune responses provide two critical “improvements” over the innate responses: the memory response, allowing the immune system to react more quickly and effectively to a previously seen pathogen, and response maturation, allowing for a more targeted, higher affinity response to a pathogen. These differences from the innate responses can also be taken advantage of by invading pathogens in the form of dominant epitopes or antigenic variation, both of which can mislead the immune system into making ineffective responses.

Evasion of CTL responses

The cytotoxic T-lymphocytes are CD8+ T cells that can directly lyse and induce apoptosis in infected cells, as well as releasing cytokines such as IFN-γ, TNF-α and TNF-β. Presentation of non-self antigens in complex with MHC class Ⅰ on the surface of infected cells along with co-stimulatory molecules can activate this killing and the γ-HVs have devised several ways of preventing this from occurring as outlined in Table 31.6.

Table 31.6. Viral CTL Regulators. CD8+ T-cell responses play a critical role in the elimination of virally-infected cells. Both human γ-herpesviruses encode multiple gene products with the potential to alter the ability of host CTLs to recognize and eliminate virally-infected cells. The open reading frame, product and potential function are listed for each, with additional details in the text.

Table 31.6

Viral CTL Regulators. CD8+ T-cell responses play a critical role in the elimination of virally-infected cells. Both human γ-herpesviruses encode multiple gene products with the potential to alter the ability of host CTLs to recognize and eliminate virally-infected (more...)

KSHV encodes two genes, K3 (MIR-1) and K5 (MIR-2), whose products are able to down regulate MHC class Ⅰ from the surface. Respectively, they are the eleventh and fourteenth Orfs from the left end of the genome, encoding products with approximately 40% identity (Russo et al., 1996). They are early lytic proteins and showed increased expression in TPA treated PEL cells (Sun et al., 1999). Work from Krishnan et al., (2004) demonstrated that the K5 gene product is also expressed very rapidly after infection with KSHV. The levels of this protein then slowly decline over the next several days. The K3 and K5 proteins are both type Ⅲ integral membrane proteins containing a zinc-binding Really Interesting New Gene (RING-CH) sequence at the N-termini, two hydrophobic transmembrane regions and a series of protein motifs important in cellular trafficking in the C-terminus (Coscoy and Ganem, 2000; Ishido et al., 2000; Means et al., 2002; Sanchez et al., 2002). Both have been shown to insert into the ER membrane such that the N- and C-termini are projecting into the cytosol (Sanchez et al., 2002). The PHD domains of these proteins resemble those found in a number of E3 ubiquitin ligases and are capable of mediating self ubiquitinylation when fused to the GFP protein (Coscoy et al., 2001). While the exact mechanism of MHC class Ⅰ molecule down regulation is still only partially understood, this ability of K3 and K5 to act as an E3 ligase seems critical. The transmembrane regions of these two proteins probably play at least two roles. First, they define the target specificity. K3 is able to down regulate multiple HLA haplotypes, whereas K5 down-regulates a much more restricted set. However, K5 is additionally able to target the cellular B7.2 costimulatory molecule and ICAM-1 adhesion molecule for down-regulation (Coscoy and Ganem, 2000; Ishido et al., 2000; Means et al., 2002; Sanchez et al., 2002). The selection of targets is regulated by the transmembrane domains (Sanchez et al., 2002). Second, these sequences probably allow K3 and K5 multimerization, although it isn’t clear what role this plays in their function (Sanchez et al., 2002). Downstream of the transmembrane regions, both contain a conserved series of residues identified as being important in protein:protein interactions and cellular trafficking (Means et al., 2002; Sanchez et al., 2002). Several of these motifs, including a Y–X–X–φ endocytosis sequence, direct internalization of the target proteins from the cell surface into the trans-Golgi network (TGN) (Means et al., 2002). From there other motifs, primarily two stretches of acidic amino acids, redirect the target proteins to the endosomal/lysosomal compartment where they undergo destruction by the ubiquitin:proteasome system (Lorenzo et al., 2002; Means et al., 2002). Without MHC class Ⅰ on the cell surface, no peptides are presented to induce CL activation and K3/K5 expressing cells are able to escape killing (Ishido et al., 2000) (Fig. 31.5). Down regulation of ICAM-1 likely also reduces the non-specific surveillance of cells by CD8+ effectors.

EBV also regulates MHC class Ⅰ presentation of viral peptides. EBV nuclear antigen (EBNA)-1 is a latent viral protein and contains a glycine, alanine repeat (GAR) region and plays a critical role in maintenance and segregation of the viral episome (Hennessy and Kieff, 1983; Yates et al., 1984). The GAR region inhibits proteasome functioning, greatly decreasing presentation of EBNA-1 peptides derived from full-length protein, as well as limiting EBNA-1 mRNA translation (Levitskaya et al., 1997; Yin et al., 2003; Blake et al., 1997). This has the effect of keeping the levels of EBNA-1 low, but stable, in latently infected cells. In addition to proteasome-independent presentation of EBNA-1 peptides, most likely by professional APCs that take up dead or dying EBV-infected cells, EBNA-1 peptides are probably also generated by degradation of aberrant translation products in a proteasome-dependant manner (Khanna et al., 1996; Lee et al., 1996; Lautscham et al., 2003). Several papers have now shown that the anti-EBNA-1 CD8+ T-cells are present in most EBV-infected healthy individuals, however, only with more sensitive IFN-γ detection are these CTL detected and not with less sensitive killing assays (Meij et al., 2002; Lee et al., 2004; Tellam et al., 2004; Voo et al., 2004). Given this new information the overall role of EBNA-1 in protection from CD8+ T-cell responses needs to be evaluated. There is a possibility that EBV has evolved a mechanism for allowing limited CTL recognition of infected cells in order to maintain its latency program.

KSHV, like EBV, seems to have evolved a similar mechanism for blocking CTL recognition of its major latency-associated protein, LANA. Like EBNA-1 for EBV, LANA acts in maintenance of the KSHV episome by tethering it to the cellular chromosome (Barbera et al., 2006). Also like EBNA-1, LANA contains long repetitive sequences, that can be broken up into three sections composed of repeats of aspartic acid and glutamic acid, glutamine and glutamic acid, or aspartic acid and glutamine, respectively. These repeat sequences are capable of blocking the processing of CTL epitopes in cis, but not in trans (Zaldumbide et al., 2006). Further exploration of this function by the Moore group has demonstrated that the block occurs both through synthesis retardation and reduced defective ribosomal product (DRiP) formation and processing (P Moore, personal communication). The overall contribution of this viral impediment to MHC class Ⅰ antigen presentation on viral immune escape still requires further investigation.

The BCRF1 protein, described earlier in this chapter as a deregulator of the interferon responses, is also able to block MHC class Ⅰ-dependent CTL responses against viral antigens (Fig. 31.5). This protein, like cellular IL-10, is able to down regulate the transporter associated with antigen processing subunit 1 (TAP1) and a proteasome subunit, low molecular weight protein 2 (LMP2), but not the TAP2 protein (Zeidler et al., 1997). The TAP proteins act to transport peptides from the cytosol into the ER, where they can be loaded onto MHC class Ⅰ, while LMP2 is a constituent of the proteasome, which degrades antigenic proteins into peptides. After treatment of primary tonsillar B cells with human or viral IL-10 both TAP1 and LMP2 mRNA levels were seen to decrease dramatically (Zeidler et al., 1997). So, EBV has hijacked an immunoregulatory cytokine, which likely plays a role in preventing autoimmune responses, to dramatically decreases the CD8+ CTL antiviral responses (Fig. 31.5).

Evasion of CD4+ T helper cell and B cell responses

The CD4+ T helper (Th) cells are able aid in the recognition and elimination of pathogens in multiple ways. The Th1 cells, after recognition of foreign peptides complexed with MHC class Ⅱ, are able to activate macrophages, as well as activating B cells to produce certain subclasses of antibodies. The CD Th2 cells, in an analogous way, are able to drive the activation and differentiation of B-cells such that they produce a wide variety of immunoglobulins. The B-cell responses are closely tied to this activation of the CD4+ T helper cells and binding of non-self peptides by MHC class Ⅱ. On the surface of B cells, the B cell antigen receptor (BCR) can bind to antigens, which are then internalized and degraded into peptides that are loaded onto MHC class Ⅱ. These complexes are transported to the cell surface, where they can be recognized by antigen-specific Th2 cells causing the T-cell to produce both cell surface and secreted proteins. This T-cell help causes the B cell to proliferate and its progeny to differentiate into antibody-secreting cells. The threshold of this proliferation and antibody production can be significantly lowered if the B cell is additionally stimulated through the B-cell coreceptor made up of CD19, CD21 and CD18. Antibodies produced by the activated, differentiated B-cells can then act to neutralize and clear free virus, as well as drive antibody-dependent cell-mediated cytotoxicity (ADCC) reactions where NK cells can target infected cells through Fc receptors on their surface.

Both KSHV and EBV have mechanisms by which they can possibly block B-cell responses as outlined in Table 31.7 and in Fig. 31.5. One component of the B-cell coreceptor, CD21, is capable of binding to C3d. The KSHV KCP/Kaposica protein drives inactivation of the complement C3 convertase and production of C3d, detailed more fully earlier in this chapter (Spiller et al., 2003). It is unclear whether this aberrant production of C3d is capable of altering B-cell responses. It is also possible that C3d is produced in order to attract CD21+ B-cells, which KSHV can then target for infection. EBV also targets CD21 through its gp350/220 envelope protein. This protein is a constituent of the viral envelope and is capable of binding to CD21 to aid in viral entry. Again, it is unclear what implications this has for anti-viral B cell responses.

Table 31.7. Viral B-cell regulators. The B-cell response is controlled both by signals given directly to the antibody-producing B-cell and signals transmitted to T-helper cells, which in turn aid the B-cell response. Both human γ-herpesviruses encode multiple gene products with the potential to alter the host’s humoral response through interfering with both of these aspects of B-cell stimulation. The open reading frame, product and potential function are listed for each, with additional details in the text.

Table 31.7

Viral B-cell regulators. The B-cell response is controlled both by signals given directly to the antibody-producing B-cell and signals transmitted to T-helper cells, which in turn aid the B-cell response. Both human γ-herpesviruses encode multiple (more...)

Much in the same way that the KSHV K5 (MIR-2) protein was able to block the anti-viral activities of the NK cells, it is also able to inhibit T-helper cell activation (Coscoy and Ganem, 2001). Both ICAM-1 and B7.2 play crucial roles in inducing T-help. The down regulation and destruction of these molecules, therefore, prevents the induction of a vigorous B cell response (Coscoy and Ganem, 2001). The presence of multiple cytokines that enhance the Th2 response, however, might diminish the immune evasion potential of this mechanism.

The EBV BZLF1 protein, earlier introduced as having a role in altering interferon responses, is able to block IFN-γ-induced MHC class Ⅱ surface expression by inhibiting the CIITA transcription factor (Morrison et al., 2001). This has the effect of shutting down T-helper cell activation, limiting the humoral response. While a similar mechanism has not been described for KSHV, the presence of multiple genes capable of interfering with the actions of IFN-γ leave open the possibility that MHC class Ⅱ induction and stimulation of T-help is being blocked in a similar manner.

Finally, the GAR region of the EBNA-1 protein of EBV was originally thought to limit the CD4+ T-cell responses. This doesn’t, however, seem to be true. Several groups have demonstrated an ability to detect strong EBNA-1 CD4+ Th1 responses in healthy individuals (Munz et al., 2000; Bickham et al., 2001; Leen et al., 2001; Paludan et al., 2002; Voo et al., 2002). These cells are capable of recognizing LCLs, EBV transformed cells and Burkitt’s lymphoma cell lines (Munz et al., 2000; Bickham et al., 2001; Paludan et al., 2002; Voo et al., 2002). Thus, the role of EBNA-1 in escape from Th and B-cell responses needs further evaluation.

Conclusions

An understanding of the mechanisms by which these viruses evade the antiviral immune responses is informative on several levels. First, by examining viral inhibition of specific immune responses much can be learned about regulation and functioning of the immune system. Second, virally-associated neoplasms can be viewed as aberrations where the normal balance between control of the virus by the host immune responses and avoidance of those same responses by the virus has been corrupted. By understanding what responses are capable of controlling viral proliferation in the case of the immunocompetent host then more effort can be directed at vaccinating to induce protective responses.

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