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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 30KSHV manipulation of the cell cycle and apoptosis


Molecular Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA USA

Disruptions of cell cycle and apoptotic regulatory control are primary hallmarks tumor cells. It is therefore not surprising that Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV8), a tumor virus, encodes viral proteins targeting these cell growth regulation mechanisms. The extent and range of KSHV genes devoted to manipulating these processes is, however, remarkable.

As described in previous chapters, herpesviral structural and replication-related genes are highly conserved among the herpesviruses, including KSHV. In contrast, regulatory genes generating proteins that modify the cellular environment – particularly during latency – are generally unique to each virus. As will become evident in this chapter, even though KSHV and EBV are closely related to each other, there are few sequence homologies among the oncogenes and non-structural regulatory genes found in the two viruses. Despite this, there is a striking functional similarity between the two viruses (Table 30.1). EBV encodes multiple highly evolved transcription factors and signaling proteins that induce many of the same cellular genes that KSHV has pirated into its genome. Further, once herpesvirus targeting of a cellular pathway has been found for one herpesvirus (e.g., HSV-1 downregulation of MHC I surface expression, Hill et al., 1994), searching for functional similarities among other herpesviruses has been particularly rewarding (e.g., Coscoy et al., 2000). It is therefore not surprising that KSHV and EBV share pathways for cell transformation although they achieve this through very different mechanisms.

Table 30.1. Functional similarities between KSHV, EBV and other tumor viruses.

Table 30.1

Functional similarities between KSHV, EBV and other tumor viruses.

Several general principles for KSHV regulatory gene functions that affect cell transformation and tumorigenesis can be made with the important caveat that exceptions exist to each rule.

  1. Although there is little or no sequence homology among oncogenes encoded by different tumor viruses, the cellular targets for viral oncogenes are frequently conserved (Table 30.1). For example, direct inhibitors of p53 from KSHV, adenoviruses, polyomaviruses, and papillomaviruses have no apparent similarity to each other but all of these viral proteins target and inhibit p53 functions.
  2. KSHV proteins encoded by viral genes pirated from the cellular genome have similar functions to their cellular counterparts. They generally differ in their regulation rather than their function. For example, the KSHV vCYC protein acts as D-type cyclin in cells but unlike cellular cyclins it is resistant to inhibition by cyclin-dependent kinase inhibitors but are modified to escape normal cellular regulation. The evolution of entirely new KSHV gene functions is uncommon and differences between cellular and KSHV homologues lie primarily in their expression and regulation (for an exception, however, see description of ORF36 mRNA shut-off functions in Chapter 56).
  3. KSHV targeting of cellular tumor suppressor pathways also inhibits host defenses against viral infection which indeed may be the principle benefit to the virus for these proteins (Moore & Chang, 1996, see also Chapter 31). Signaling pathways controlling of tumor cell growth, such as Fas-FasL death receptor signaling, also critical for both innate and adaptive immune responses, and are targeted by putative KSHV oncoproteins.
This chapter describes the effects of individual KSHV proteins on cell cycle control, apoptosis, and cellular transformation. It is, by necessity, an artificial division of these functions, since cell growth control mechanisms are intimately tied into other aspects of the viral lifecycle such as maintenance of latency (Chapter 24) and immunoevasion (Chapter 31). Caution is warranted given the limitations to our ability to study how KSHV contributes to cancer. Our understanding of viral effects on cell growth are generally based on in vitro cell culture systems, e.g., PEL cell cultures, and on the study of individual genes in isolation. Much can be learned from this reductionist approach, but it is important to keep in mind that results from the benchtop do not always translate to the bedside, which is more fully addressed in Chapters 50 and 56).

Cell cycle and programmed cell death regulation

The normal cell cycle is actively regulated through specific protein-kinase regulatory subunits, cyclins (Murry, 2004), that are cyclicly expressed during the different phases of the cell cycle and degrade as the cell exits each phase (Fig. 30.1). Cyclins regulate the periodic oscillations of the cell cycle by coupling to cyclin-dependent kinases (which tend to be constitutively expressed) to phosphorylate specific cell cycle regulatory targets, for example, the retinoblastoma protein (pRB1) controlling expression of genes necessary for transit from G1 into S phase. The cyclin component of the dimeric complex generally serves as the targeting moiety directing CDK phosphorylation to specific substrates.

Fig. 30.1. A schematic diagram of cell cycle control interactions between the G1/S checkpoint retinoblastoma protein (pRB1) and p53.

Fig. 30.1

A schematic diagram of cell cycle control interactions between the G1/S checkpoint retinoblastoma protein (pRB1) and p53. (a) Normal feedback control allows pRB1 to negatively regulate entry into the S phase by inhibition of E2F-regulated DNA synthesis (more...)

Some cyclins such as cyclin A and the D-type cyclins do not appear to be essential for intrinsic cell cycle periodicity but serve to regulate it (Kozar et al., 2004). pRB1 (a member of a family of related proteins that also includes p130) is a transcriptional repressor that binds and inactivates E2F family transcription factors involved in transcription of genes required for DNA synthesis prior to S phase. These enzymes include dihydrofolate reductase, thymidine kinase, and several other nucleotide synthesis enzymes expressed during the G1/S phase transition and have been pirated by KSHV (Russo et al., 1996). When pRB1 is hyperphosphorylated by cyclin D-CDK4 or CDK6, it is inactivated and releases E2F allowing expression of DNA synthesis enzymes. Thus pRB1 is a critical regulator for the transition between G1 and S phase and controls the cellular environment to prevent unscheduled DNA synthesis. Another substrate phosphorylated by cyclin-CDK complexes is the anaphase-promoting complex (APC), which controls chromosome separation during mitosis and acts as a checkpoint protein at the G2/M cell cycle transition.

Viral manipulation of cell cycle checkpoint proteins could be an obvious advantage to a virus, particularly during lytic viral replication when large amounts of viral DNA must be generated. But, interference with normal cell cycle regulatory circuits often activates cell cycle arrest or programmed cell death (apoptosis) signaling. Cell cycle and apoptotic pathways are characterized by extensive feedback interactions that not only serve to prevent tumor cell generation but also to inhibit viral replication within cells (Takaoka et al., 2003). Viral inhibition of pRB1, for example, results in p53 activation through p14ARF and MDM2 (Fig. 30.1). Thus, overexpression of individual cellular or viral oncoproteins may paradoxically result in cell cycle arrest or cell death rather than proliferation, as is the case for cellular cMYC, or adenoviral E1A (de Stanchina et al., 1998, Debbas and White, 1993; Zindy et al., 1998). Because of this feedback regulation, viral proteins that initiate dysregulated cell cycle entry can be mistaken to have the exact opposite effect, e.g., cell cycle arrest or apoptosis. Caution must be used to interpret the consequences of viral protein expression in the context of the actual viral lifecycle in which multiple KSHV proteins may be acting in concert.

Cell cycle dysregulation during viral latency

Although lytic KSHV replication may contribute to tumor formation in humans though paracrine mechanisms (see Chapter 56), most interest is focused on the latent viral genes constitutively expressed in tumor cells as oncogenes. Whereas latent virus replication is compatible with cell expansion, virion production generally leads to cell death. As described in Chapter 28, the division between “latent” genes and “lytic” genes, however, has become increasingly blurred. Intracellular notch (Chang et al., 2005) or interferon signalling (Chatterjee et al., 2002) can activate expression of genes such as K1 (KIS) and K2 (vIL-6) that are traditionally referred to as lytic genes without full lytic cascade activation and cell death. Notch signaling in particular appears to be responsible for the Type Ⅱ pattern of KSHV gene activation (Sarid et al., 1998), markedly increasing the number and range of KSHV genes having potential to play a role in KSHV-induced tumorigenesis. Intriguingly, the latent antigen LANA1 has been reported to activate notch signaling and intracellular notch activity is high in resting PEL cells (Lan et al., 2006).


The major latency locus on the right-hand end of the genome (Fig. 30.2) encodes three open reading frames (ORFs K13, 72 and 73) for the vFLIP, vCYC and LANA1 proteins. An additional long transcript expressed by polyadenylation site read-through from this promoter is processed into at a number of miRNAs that are also constitutively expressed (Pfeffer et al., 2005; Cai et al., 2005). While the viral or cellular targets for these miRNAs are unknown, they are of particular interest since cellular miRNAs have been closely associated with cancer cell regulation (Esquela-Kerscher and Slack, 2006). Recent studies also reveal the complexity of gene expression at this locus with some transcripts extending to the K12 region. Some overlapping transcripts for ORFs K12, K13, 72 and 73 have been shown to be induced during lytic replication demonstrating that the widely-held view that these genes are expressed in a static fashion is incomplete (Cai and Cullin, 2005; Pearce et al., 2005).

Fig. 30.2. Diagram of the KSHV major latency locus.

Fig. 30.2

Diagram of the KSHV major latency locus. Northern blots are shown for the major genes in this region under conditions of lytic induction (TPA) or viral DNA synthesis inhibition using the DNA polymerase inhibitor, phosphonoformic acid (PFA). The genes (more...)

ORF73 encodes LANA1 (Latency-associated nuclear antigen)1, first discovered as a serologic antigen useful for detecting KSHV infection (Moore et al., 1996), that functions to maintain the viral episome by tethering it to cellular chromosomes during mitosis (Ballestas et al., 1999, see Chapter 24). LANA is mainly expressed from a polycistronic transcript (LT1) that includes vCYC and vFLIP (Figure 30.2). These two latter proteins are also expressed from a second transcript (LT2) that originates from the same promoter but splices out ORF73. The latency promoter is cell cycle-regulated with highest expression during late G1 (Sarid et al., 1998) and LANA1 positively autoregulates its own expression as well (Jeong, et al., 2004). Although LANA1 and vCYC proteins are translated from LT1 and LT2 respectively, vFLIP translation requires an internal ribosomal entry site (IRES) located at the 3’ end of the vCYC message (Grundhoff and Ganem, 2001; Bieleski and Talbot, 2001; Low et al., 2001). Outside of the major latency locus, the ORF K10.5 gene product, vIRF3 or LANA2, is also constitutively expressed in KSHV-infected hematopoeitic cells but not KS tumor cells (Cunningham et al., 2003). Other KSHV genes, including K12 (kaposin) are expressed during latency but are also induced during lytic replication and by other transcriptional activation, such as notch-signaling (Chang et al., 2005).

Table 30.2Major KSHV proteins affecting cell cycle control machinery

Protein Gene Target(s)
Latency LANA1 ORF73 pRB1
vCYC ORF72 pRB1, p27, ORC1, H1, Cdc25a
Lytic or Induced vGPCR ORF74 Akt, SAPK pathways
KIS ORF K1 ITAM signaling
vIL-6 ORF K2 Interferon, IL-6 signaling
vMIP 1–3 ORFs K4, 4.1 and 6 Angiogenesis
Lytic K-bZIP (RAP1) ORF K8 C/EBP-α, p21

LANA1 is a large protein (ca. 150 kDa) composed of basic, glutamine-rich amino- and carboxyl-terminal domains separated by a highly acidic, aspartic- and glutamic acid-rich repeat region that includes a leucine zipper domain (see Chapter 24). Because of its highly charged, amphipathic structure it runs as a 220–224 kDa doublet on denaturing gel electrophoresis. This multifunctional protein is reminiscent of the SV40 virus large T-antigen (LT ag), since it tethers the episome to cellular DNA during mitosis and also disrupts both cell cycle and p53-mediated apoptosis.

LANA1 abrogates cell cycle arrest through its binding to at least two of the many cellular interaction partners for LANA1 that have been described. Radkov and colleagues (Radkov et al., 2000) found that LANA1 directly binds the hypophosphorylated (active) form of RB1, inhibiting RB1’s ability to serve as a transcriptional repressor of the E2F family. LANA1 binds the pocket region of RB1, but not the related RB1-like protein p130, through interactions with a central region that includes the leucine zipper domain. This effectively sequesters RB1, allowing E2F transactivation (Figure 30.1). Dysregulation of the G1/S checkpoint by LANA1 can be functionally demonstrated rodent cell transformation assays. While LANA1 expression alone does not enhance cellular transformation, oncogenic cooperativity occurs when LANA1 is coexpressed with the activated H-Ras oncogene.

Aside from direct inhibition of RB1, LANA1 as a second pro-mitogenic activity through its ability to activate the Wnt signaling pathway. Hayward and colleagues identified glycogen synthase kinase – 3β (GSK-3β) as a protein interactor with LANA1 through yeast two-hybrid screening (Fujimuro and Hayward, 2003; Fujimuro et al., 2003). GSK3-β normally phosphorylates β-catenin causing the cytoplasmic sequestration of this proto-oncoprotein. LANA1, however, inhibits GSK-3β regulation of β-catenin allowing it to accumulate in the nucleus and transactivate responsive promoters, including the cMYC promoter. cMYC has diverse mitogenic activity and activates the hTERT promoter, which may contribute to the ability LANA1 to activate telomerase activity in KSHV infected cell lines (Verma et al., 2004; Wu et al., 1999). GSK3-β inhibition could potentially also indirectly modulate cell cycle entry through its ability to phosphorylate D-type cyclins resulting in their cytoplasmic accumulation (Verschuren et al., 2004b). These secondary consequences of LANA targeting of Wnt pathway signaling are speculative and remain to be examined but suggest novel and unexplored ways that LANA can contribute to cell transformation. As is the case for many KSHV signaling pathways, EBV has also been shown to stabilize β-catenin showing conservation of cell signaling pathway targeting by the two vriuses (Hayward et al., 2006).

Viral cyclin (vCYC)

While LANA1 has no homologue in the human genome, KSHV also uses its pirated cyclin to hijack cell cycle regulatory control mechanisms. The vCYC protein (ORF72) (Cesarman et al., 1996; Chang et al., 1996) is expressed together with LANA1 from the major latency locus. As previously described, cellular cyclins positively regulate various stages of the cell cycle by partnering with CDKs to phosphorylate specific cell cycle components. KSHV vCYC retains sequence similarity to the D-type cyclins (there are three cellular D cyclins-D1, D2, and D3 which have overlapping and apparently redundant activities), which target CDK4 and CDK6 to hyperphosphorylate RB1, thereby inhibiting this inhibitor of E2F-induced transcription. KSHV vCYC partners almost exclusively with CDK6 to achieve this effect (Chang et al., 1996; Godden-Kent et al., 1997; Li et al., 1997), initiating illicit S phase entry and DNA replication (Laman et al., 2001).

Although vCYC is structurally similar to D-type cyclins, several features of the protein are unique. Unlike D-type cyclins, vCYC (also referred to as K-cyclin) targets cell cycle control proteins that are more typical targets of other cyclins such as cyclins A and E which couple to the CDK2 kinase. These targets include histone H1, the CDKI p27, and Cdc25a, as well as ORC1 and Cdc6 (Ellis et al., 1999; Laman et al., 2001; Mann et al., 1999) (for review see Verschuren et al., 2004b). Unlike cellular cyclin D/CDK6 complex, which normally requires CDK6 phosphorylation through the action of a CDK-acitvating kinase (CAK), the vCYC/CDK6 is fully active in an unphosphorylated form (Child and Mann, 2001; Kaldis et al., 2001).

The vCYC gene, ORF72, like the other genes encoded in the major latency locus, is expressed during late G1 in a cell cycle-dependent fashion (Sarid et al., 1999). Although direct measurement of vCYC protein levels are difficult, vCYC lacks the cyclin destruction box motif that targets cyclins for rapid protein turnover (Klotzbucher et al., 1996) suggesting that the viral protein may be long-lived and active at other portions of the cell cycle including the G2/M checkpoint (Van Dross et al., 2005). Also absent from the viral protein are motifs required for docking to nuclear export proteins, which may indicate that vCYC abnormally accumulates in the nucleas and may escape regulations imposed on cellular cyclin proteins (Verschuren et al., 2004b). This is supported by transgenic mouse experiments (see below) in which constitutive vCYC expression leads to defects in chromosome segregation, abnormal cytokinesis and polyploidy (Verschuren et al., 2002). Surprisingly, vCYC also phosphorylates and inactivates the antiapoptotic cellular protein BCL-2, but not the corresponding KSHV BCL-2 homologue, contributing to the pro-apoptotic properties of this protein when overexpressed in cells (Ojala et al., 2000).

Another critical difference between cellular cyclins and vCYC is that vCYC escapes from normal CDK inhibitor (CDKI) control. CDKIs, including p21 and p27 and members of the p16Ink4a family, act to inhibit cyclin-dependent phosphorylation and are a critical link for transmitting cell arrest signaling from p53 to the cell cycle machinery. vCYC/CDK6 is resistant to p21 and p27 CDKI inhibition (Swanton et al., 1997, 1999), but is still inhibited by Ink4 unless CDK6 is phosphorylated through the action of CAK (Jeffrey et al., 2000). This has allowed crystallographic analysis of the trimolecular vCYC/CDK6/p18Inkb structure (Fig. 30.3), which has been tremendously informative for understanding the structural basis for vCYC regulation as well as regulation of the cellular cyclins. vCYC phosphorylation of p27 also diminishes cellular levels of this inhibitor protein, contributing to positive cell cycle regulation. In summary, although vCYC has similar functionality to cellular cyclins, modifications to this protein allow the virus to escape normal cell cycle regulatory constraints and to couple CDK6 phosphorylation to RB1 and other cell cycle components (for review, see Mittnacht and Boshoff, 2000; Verschuren et al., 2004b).

Fig. 30.3. The structure of the vCYC (purple), CDK6 (cyan), p18Inkb (yellow) complex from side (a) and top (b) views, compared to cellular cyclin A (purple), CDK2 (cyan) side (c) and top (d) views.

Fig. 30.3

The structure of the vCYC (purple), CDK6 (cyan), p18Inkb (yellow) complex from side (a) and top (b) views, compared to cellular cyclin A (purple), CDK2 (cyan) side (c) and top (d) views. Unlike cellular cyclins, the regulatory T-loop of CDK6 is excluded (more...)

A potential role for vCYC in cell tranformation and carcinogenesis has been uncovered using transgenic mice in which vCYC is expressed under an Eμ promoter (Verschuren et al., 2002, 2004a). Overexpression of vCYC both induces dysregulated DNA synthesis and leads to p53-dependent apoptosis. One mechanism by which this could occur is a circuit in which RB1 inactivation leads to E2F activation of p14ARF – a potent activator of p53 acting through MDM2. This, however, does not seem to be the case since p53-induced apoptosis is not reduced by mating the transgenic vCYC mice onto a p19ARF-null background. Instead, vCYC appears to dysregulate the G2/M checkpoint resulting in dysregulated cytokinesis and aneuploidy that in turn activates p53 through DNA-damage response pathways. When mice expressing vCYC are mated with p53-null mice, progeny develop lymphomas at an accelerated rate.

Other KSHV mitogenic signaling proteins

KSHV also possesses a number of proteins which act through mitogenic signaling pathways to achieve similar effects. Mitogenic signaling can occur through diverse signaling pathways which act on common regulatory points to induce cell cycle entry, such as activation of cyclin-dependent phosphorylation of RB1 (Sherr, 2004). While most of these molecules are thought to be expressed only during active lytic replication, evidence suggests that they have more complicated patterns of expression (see Chapter 28) in that at least several of them, such as the vIL-6 and the KSHV-encoded chemokines (Moore et al., 1996; Parravicini et al., 2000), are expressed at low levels during true viral latency (at least in tissue culture where the process can be readily examined) and are further activated during lytic viral replication or in response to specific signaling pathways. This is a similar pattern of expression to the EBV LMP1 protein. It is unclear what, if any, effects these mitogenic factors have during latency but these pathways have also received renewed interest related to the possibility that lytic virus replication contributes to the tumorigenesis, particularly in KS tumors (described more fully elsewhere in this volume).

Viral g-protein coupled receptor (vGPCR)

The best-studied example of a KSHV mitogenic signaling molecule is the vGPCR (ORF74), a seven-spanning G-protein coupled receptor that is expressed at early phases during lytic replication (Cesarman et al., 1996). vGPCR is a constitutively active CXC receptor (Chiou et al., 2002; Kirshner et al., 1999), which activates MAPK, p38, Akt and NF-κB pathways resulting in expression of angiogenic factors, such as VEGF, and in cell transformation (Bais et al., 1998; Cannon et al., 2003; Masood et al., 2002; Montaner et al., 2001; Polson et al., 2002). Although constitutively active, evidence suggests that its growth promoting activity is enhanced by host ligand binding (Holst et al., 2001). The principal interest in this protein comes from the unique phenotype that it generates in transgenic mice which was first demonstrated by Lira and colleagues (Yang et al., 2000) but has been confirmed using a variety of experimental systems by others (Guo et al., 2003; Montaner et al., 2003).

In these first experiments, vGPCR was expressed under control of the CD2 promoter, resulting in diffuse hematopoietic expression of the viral protein. Surprisingly, this resulted in endothelial tumors pathologically resembling Kaposi sarcoma tumors. These and similar results by Montaner and colleagues (Montaner et al., 2003) suggest that KS tumors, unlike primary effusion lymphomas, may actually be dependent on active lytic viral replication and that KS tumor cell proliferation occurs in trans due to paracrine factors released by infected cells undergoing lytic replication. This is a unique pathogenic model in which paracrine factors, rather than endogenous genetic changes, are responsible for the neoplastic phenotype (Cesarman et al., 2000).

Several findings, however, complicate this view. It is evident that virtually all tumor cells in KS tumors are infected with KSHV and so paracrine-effects of lytic replication appear to act in concert with endogenous viral gene expression to result in tumor cell outgrowth (Parravicini et al., 2000, Katano et al., 2000). KS development can be effectively prevented by antilytic DNA pol inhibitors, such as ganciclovir (Martin et al., 1999), but there is no current evidence that these drugs have any effect on established KS tumors (Little et al., 2003). Further, clinical studies suggest that some KS tumors arising during transplantation are donor derived (Barozzi et al., 2003). Since these donors were ostensibly healthy, the prototumor was primarily latent, or at least subclinical, in the donor prior to the transplantation. Studies of cell and virus monoclonality do not clarify the origin of KS pathogenesis since both cellular monoclonality and multiclonality have been reported. KS tumors have KSHV terminal repeat patterns that are oligoclonal or monoclonal, with the possibility that tumors evolve into a monoclonal pattern over time (Judde et al., 2000; Russo et al., 1996). The role for paracrine-induced proliferation from vGCPR or other viral proteins may become clearer as KSHV gene regulation outside of the latent-lytic expression pattern is explored.

K1 protein

On the opposite end of the KSHV genome (see Chapter 28), a second membrane signaling protein encoded by ORFK1, also called KIS (KSHV ITAM signaling protein), has strong mitogenic activity when expressed in cells. K1 protein is a type 1 transmembrane protein that aggregates through ectodomain disulfide bonds into a signaling complex (Lee et al., 1998b). The cytoplasmic tail of the protein contains two immunoreceptor tyrosine signaling motifs (ITAMs) which recruit SH2-containing signaling kinases; NFAT, syk, vav and other downstream signaling effectors have been shown to be activated by K1, resulting in Akt signaling activation (Lagunoff et al., 1999, 2001; Lee et al., 1998a, 2003; Tomlinson and Damania, 2004, Wang et al., 2005). As a consequence of its mitogenic signaling activities, K1 transforms rodent fibroblasts and primary endothelial cells in vitro and when substituted into a herpesvirus saimiri backbone, induces lymphomas in rhesus macques (Lee et al., 1998b, Wang et al., 2005).

Clues to the functional advantage of this signaling protein for the virus, come from overlap between K1 signaling and signaling through the B cell receptor (BCR). The BCR is active as a non-specific innate immune signaling pathway. Intriguingly, K1 causes ER retention and degradation of the BCR, suggesting that K1 may serve as a decoy molecule after downregulation of this pathway (Lee et al., 2000). A consequence of K1 expression is induction of paracrine angiogenic factors including vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), analogous to the paracrine mitogenic induction that can occur with vGPCR (Wang et al., 2004). The immunoevasion/mitogenic properties of K1 have analogy, together with the KSHV LAMP1 protein, to properties of EBV membrane proteins, LMP1 and LMP2 (Damania et al., 2000).

Virus-encoded chemokines and cytokines

In addition to both vGPCR and K1 protein, which induce secretion of proliferative cytokines, KSHV itself encodes three secreted chemokines, vCCL1 (ORF K6), vCCL2 (ORF K4) and vCCL3 (ORF K4.1), formerly known as vMIP-I/MIP-1a, vMIP-Ⅱ/MIP-1b and vMIP-Ⅲ/BCK, respectively and a functional, secreted vIL-6 (ORF K2) cytokine. The chemokines are believed to act to polarize local immune responses towards a Th2 phenotype. vCCL2 initiates a strong chemotactic response through CCR3 activation (Boshoff et al., 1997), while vCCL1 and vCCL3 activate CCR8 (Dairaghi et al., 1999, Endres et al., 1999) and CCR4 receptors (Stine et al., 2000). All three chemokines have angiogenic activity and stimulate endothelial and B-lymphocytic proliferation (Moore et al., 1996; Stine et al., 2000). While they are generally not expressed in PEL cells during latency, they may play a role in mitogenesis in KS tumors.

Like K1 protein, KSHV encoded vIL-6 has both immune evasion and cell cycle regulatory properties (Moore et al., 1996; Nicholas et al., 1997) (described in more detail in Chapter 31). vIL-6 is a secreted cytokine similar to the human cytokine (25% identity, 62% similarity) that activates IL-6 signaling pathways by binding directly to the gp130 signal transducer molecule without requiring interaction with the IL-6 specific recepor, gp80 (Burger et al., 1998; Chow et al., 2001; Molden et al., 1997; Mullberg et al., 2000; Osborne et al., 1999). Although this has not been directly examined, it is likely that the viral protein activates the same signaling pathways as hIL-6, resulting in RB1 hyperphosphorylation and mitogenesis (Urashima et al., 1996, 1997; Zhu et al., 1994). Studies of a non-adapted tissue culture PEL cell line, BCP-1, demonstrate that the cells are autocrine dependent on hIL-10 and vIL-6 (Jones et al., 1999), and can reinitiate DNA synthesis for serum-starved PEL cells (Chatterjee et al., 2002).

The role of vIL-6 in the lifecycle of KSHV reveals the intimate connection between cell cycle regulation and early innate immune responses (Chatterjee et al., 2002). Type Ⅰ interferon signaling in PEL cells causes upregulation of p21 CDKI and initiates arrest. The vIL-6 promoter, however, has transcription elements responsive to interferon signaling and is simultaneously up-regulated. Evidence suggests that vIL-6 can block interferon signaling at the receptor resulting in a negative feedback loop that protects infected cells from cell-cycle arrest effects of interferon. Interferons are activated by viral infection and the autocrine loop formed by vIL-6 appears to block antiviral effects induced by KSHV infection itself. A consequence of vIL-6 hypersecretion may include neighboring cell proliferation as is seen in multicentric Castleman’s disease (Parravicini et al., 1997). As an interesting aside, this demonstrates that a virus can sense and modify its environment, a property referred to as irritability, that is part of the fundamental definitions for living organisms.

Inhibition of cell cycle progression: K-BZIP/RAP

The proteins thus far described for KSHV act on cell cycle checkpoints to prevent cell cycle arrest. KSHV k-BZIP (also known as replication associated protein, RAP) encoded by ORF K8, paradoxically has opposing effects on cell cycle regulation. K-BZIP is an early spliced gene (corresponding by weak sequence homology to the EBV transactivator Zta or ZEBRA) possessing a basic-leucine zipper (bZIP) (Gruffat et al., 1999; Lin et al., 1999; Seaman et al., 1999). This protein interacts with p53 and may sequester p53 (together with the other major lytic transactivator RTA (Gwack et al., 2001b)) to promyelocytic leukemia (PML) bodies, presumably as a means of delaying p53-dependent apoptosis during the early phases of lytic reactivation (Park et al., 2000). Despite this, K-bZIP causes cell cycle arrest through induction of the CDKI p21, a downstream target of p53, and CCAAT/enhancer binding protein-α (C/EBP-α) resulting in G1 arrest during lytic replication (Wang et al., 2003a,b; Wu et al., 2003). K-bZIP is phosphorylated by CDKs (Polson et al., 2001) and also directly interacts with cyclin A/CDK2 complexes contributing to G1 arrest during early lytic replication (Izumiya et al., 2003).

The reasons for this effect remain speculative. Virus-induced cell cycle arrest may seem counterintuitive – particularly in view of the limited resource hypothesis for oncogene teleology developed from analyses of small DNA tumor viruses (Braithwaite and Russell, 2001; Russell et al., 2004), since S phase entry is thought to be required for viral DNA replication. Entry into a “senescent” phenotype, however, might have protective effects in preventing premature apoptosis during lytic replication. It is also unclear if expression of the lytic phase KSHV DNA synthesis enzymes whose cellular counterparts are under E2F-control (e.g., ribonucleotide reductase, thymidylate synthase, dihydrofolate reductase and thymidine kinase) can generate a quasi-S phase state in the face of K-BZIP induced cell cycle arrest. Conceivably, this may allow viral DNA replication during stasis in cellular DNA replication. K-BZIP acts during lytic replication whereas LANA1 and vCYC act during latency (possibly during lytic replication as well) indicating that the different phases of the viral life cycle require different cell cycle manipulations.

KSHV inhibition of apoptosis

Interference with cell cycle checkpoints activates cellular apoptotic pathways through p14ARF and other less well-defined mechanisms, presumably as a means to prevent tumor cell formation (Sherr, 1998, 2004). It is therefore not surprising that KSHV encodes antiapoptotic factors that mitigate this response. What is surprising, however, is the number, range and kind of anti-apoptotic factors encoded by KSHV (Table 30.3, for review see Lagunoff and Carroll, 2003). KSHV also activates survival factors, such as NF-κB, a trait shared with EBV and other B-lymphotrophic viruses.

Table 30.3. Major KSHV proteins targeting apoptotic control machinery.

Table 30.3

Major KSHV proteins targeting apoptotic control machinery.

Apoptotic signaling is divided into intrinsic and extrinsic pathways integrated with each other through the activity of the transcription factor p53 (Fig. 30.4). Extrinsic pathways are activated through apoptotic signaling receptors, such as Fas/CD95 and the tumor necrosis factor receptor (TNFR), whereas intrinsic pathways are activated in response to cellular stress and DNA damage (Danial and Korsmeyer, 2004).

Fig. 30.4. KSHV inhibits both intrinsic and extrinsic apoptotic pathways at multiple points.

Fig. 30.4

KSHV inhibits both intrinsic and extrinsic apoptotic pathways at multiple points. Extrinsic signaling shown here is activated by cellular immune signaling (NK cell, cytotoxic lymphocyte responses) though activation of the Fas receptor. vFLIP directly (more...)

Extrinsic apoptotic signaling is principally an immune response activated through death-inducing receptors by natural killer (NK) cells and cytotoxic lymphocytes (CTL). Receptors of the TNF-Fas receptor family can have either opposing proapoptotic or antiapoptotic signaling responses depending on the mechanism of activation and the cellular context of receptor activation. Extrinsic apoptotic signaling activates caspase cascade signaling which in turn results in mitochondrial release of apoptosis mediators including cytochrome C. p53 has been implicated in increasing apoptotic receptor transcription and priming other components of these pathways (Sheard et al., 2003).

Intrinsic apoptotic signaling directly activates p53 through a series of kinase cascades, ultimately resulting in mitochondrial apoptosis. Although this characterization of this response is rapidly evolving, current evidence suggest that sensors of DNA damage activate signaling cascades that ultimately result in cell cycle arrest and repair or, failing this, apoptosis. Responses may differ between types of DNA damage (e.g., mismatch damage vs. single and double-strand breaks) that activate different repair responses including nucleotide-excision repair, base-excision repair, or homologous and non-homologous recombination (for review see Wood et al., 2001).

One of the initial responses to DNA damage recognition is binding and activation of the MRE11- Rad51-NBS (MRN) complex, which sequentially activates Chk2 and ATM phosphorylation and subsequent phosphorylation of p53 (Banin et al., 1998; Lee and Paull, 2004). The importance of this pathway to viral replication is hinted at by viruses encoding proteins that target these early responses (Weitzman et al., 2004). KSHV vIRF1, for example, binds to and inactivates ATM downstream signaling to p53 (Shin et al., 2006). p53 phosphorylation causes conformational changes that promote p53 binding to specific DNA regulatory elements to initiate transcription of pro-apoptotic protein genes, such as PUMA and NOXA-1, BH3-only members (see below) of the BCL-2 factor family, which act at the mitochondria to initiate mitochondrial apoptotic responses (Oda et al., 2000; Yu et al., 2001). These BH3-only containing BCL-2 factors bind and sequester other anti-apoptotic BCL-2 members, including BCL-2 itself and BCL-xL (Cheng et al., 2001; Schuler and Green, 2001).

Disarming the guardian: p53 inhibition

p53 has been called the “guardian of the genome” for its critical role in integrating apoptotic and cell cycle arrest signaling, most notably in response to DNA-damaging agents (Lane, 1992). p53 prevents germline transmission of mutations, since DNA damage will either cause p53-dependent arrest allowing repair prior to transmission to daughter cells or, if the damage is irreparable, commits the cell to p53-dependent apoptosis. The molecular decision-making process between apoptosis or cell cycle arrest remains unclear, although p21 has a key role in determining whether p53-activation results in arrest or cell death (Gorospe et al., 1997).

For somatic cells, the roles for p53 are less clear. As a tumor suppressor, p53 may prevent cell transformation resulting from DNA damage. More recently, evidence has accumulated that p53 also acts to prevent viral nucleic acid replication (Moore & Chang, 1998; Takaoka et al., 2003). Replicating extrachromosomal DNA may activate ATM-p53 signaling, thus serving as an intracellular innate immune response. It is now widely accepted that cellular responses limiting viral replication include apoptosis (Benedict et al., 2002; Meinl et al., 1998), although programmed cell death is not universal for all viral infections and some viruses may actually capitalize on cell dissolution during apoptosis to enhance replication (Teodoro and Branton, 1997).

As a critical integrator of cell cycle regulation and apoptotic signaling, p53 is a common target for tumor viruses that have convergently evolved very different mechanisms to inhibit this major regulatory protein (for review, see Lagunoff and Carroll, 2003). KSHV is no exception to this, and it directly targets p53 during both latency and during lytic replication. Unlike many malignancies, apoptosis in not prominent in KSHV-related disorders, p53 is expressed in tumor cells and p53 mutations do not appear to be common in KSHV-induced tumors (Katano et al., 2001b).


To balance the cell cycle dysregulation effect of vCYC and LANA1 during latency, KSHV must also inhibit p53-mediated apoptotic signaling for infected cell survival. This is most clearly seen in unopposed vCYC transfection assays which induce apoptosis, and vCYC transgenic mice which have a dramatically increased rate of lymphomagenesis in a p53-null background. LANA1 encoded by ORF73 was the first p53 inhibitor discovered in KSHV (Friborg et al., 1999), in which the carboxyl terminus of the protein was shown to interact with p53 and inhibit its transcriptional activator function. This work has since been extended to other rhadinoviruses such as herpesvirus saimiri whose ORF73 protein – while structurally different from the KSHV LANA1 protein – also inhibits p53 activity (Borah et al., 2004).


While LANA1 is expressed in all KSHV-infected cells, LANA2 (also known as vIRF3) encoded by the spliced gene ORF 10.5, is expressed exclusively in KSHV-infected hematopoeitic cells. LANA2 shares with LANA1 p53-inhibitory functions although evidence for direct interaction with p53 is less certain due to the inherent “stickiness” of the protein (Rivas et al., 2001). Transient expression of LANA2 abrogates apoptosis caused by activation of p53 signaling or by direct overexpression of p53 protein. Paradoxically, LANA2 simultaneously activates interferon transcription pathways (Lubyova et al., 2004)and inhibits NF-kB signaling pathways (Seo et al., 2004) – two signaling events that would be expected to induce lymphocyte apoptosis. The role, if any, of this molecule in PEL survival and transformation remains largely unknown.

RTA, K-bZIP and vIRF1

KSHV p53-inhibitory proteins active during lytic replication include the lytic transactivator proteins RTA (encoded ORF50) and K-bZIP (encoded by K8 and describe above), and the interferon regulatory factor homologue vIRF1 encoded by ORF K9. These three proteins appear to inhibit p53 transcriptional activity (Gwack et al., 2001b; Park et al., 2000; Nakamura et al., 2001) principally by binding to the p300/CBP family of histone acetyltransferases (HAT) that serve as transcriptional coadaptors for p53 (Gwack et al., 2001a; Hwang et al., 2001; Li et al., 2000; Lin et al., 2001). Direct binding by vIRF1 and K-bZIP to p53 may also occur. HAT activity is required to not only acetylate p53 itself, but also histones to prepare the operon for p53-directed transcription.

By sequestering HATs from the transcriptional complex, these KSHV proteins inhibit transcription not only at p53-regulated promoters but also (in the case of vIRF-1) interferon-regulated promoters (Gao et al., 1997; Lin et al., 2001; Zimring et al., 1998). K-bZIP may also directly sequester p53 to promyelocytic leukemia protein (PML) bodies rendering it inactive for participation in apoptotic signaling (Katano et al., 2001a). The use of CBP/p300 coadaptors is widespread in growth control transcriptional responses, and K-bZIP’s ability to sequester CBP/p300 has also been shown to inhibit SMAD3 transcriptional response in the TGF-beta signaling cascade (Tomita et al., 2004).

Beyond p300/CBP sequestration, vIRF1 also activates p53 degradation, possibly by enhancing the E4 ubiquitin-ligase activity of p300/CBP (Shin et al., 2006). vIRF1 has the unusual property of binding to and inhibiting ATM, as well. Thus, vIRF1 has a multiple roles in inhibiting ATM-p53 activation during viral infection.

Induction of p53-mediated apoptosis during lytic viral replication is thus postponed by the activity of several proteins expressed during the earliest phases of viral replication. This presumably forestalls early cell death to optimize virion production. Since cells undergoing full viral replication eventually undergo apoptosis, it is clear that, in the struggle between the virus and the cell, the cell eventually wins–but presumably not before the virus is able to generate infectious progeny. The actual apoptotic triggers initiated by viral replication remain unknown. One possibility is that viral DNA breaks, as a consequence of massive but inefficient viral DNA replication, initiate ATM-p53 signaling. Other possibilities include endoplasmic reticulum stress due to hijacking of cellular protein synthesis machinery or the degradation of cellular mRNA with concomitant transcriptional inhibition by the KSHV ORF 37 protein (Glaunsinger and Ganem, 2004).

Inhibition of extrinsic apoptotic signaling


KSHV down-regulation of MHC Ⅰ during both lytic (Coscoy and Ganem, 2000) and latent (Tomescu et al., 2003) viral replication leaves the infected cell open to NK cell attack (see Chapter 31). Intercellular killing is mediated by released membrane toxins (granzyme) and activation of Fas signaling. KSHV vFLIP encoded by ORF K13 potentially abrogates Fas-mediated apoptosis through two dominent-negative death-effector domains (DED) that block the formation of the death-induced signaling complex (DISC)(reviewed in Krueger et al., 2001).

vFLIP encoded by ORF K13 has generated considerable interest as an antiapoptic protein since it is expressed during latency through an IRES in the ORF 72 (vCYC) gene on LT1 and LT2 transcripts (Bieleski et al., 2004; Bieleski and Talbot, 2001; Grundhoff and Ganem, 2001; Low et al., 2001). While its caspase-inhibition functions have a clear benefit in preventing NK immune killing of an infected cell, the ability of this protein to activate NF-kB may have even greater importance in maintaining the infected tumor cell (Chaudhary et al., 1999). NF-kB is constitutively activated in PEL cells through IkB inhibitor phosphorylation due to vFLIP signaling (Field et al., 2003; Matta and Chaudhary, 2004) and this activity may inhibit BH3-only molecule-induced apoptosis (Fig. 30.4). Cesarman and colleagues have demonstrated the importance of this to PEL cell survival using specific NF-kB inhibitors which rapidly induce PEL cell apoptosis (Guasparri et al., 2004; Keller et al., 2000). Differentiating the effects of vFLIP on caspase inhibition from NF-kB activation suggests that the latter is critical for PEL cell survival in tissue culture. vFLIP activates NF-kB through direct interactions with the Ikappa B kinase (IKK) complex which targets inhibition of the NF-kB inhibitor, Ik-B (Liu et al., 2002). Evidence suggests this specifically activates an alternative NF-kB pathway that favors processing of the p52 subunit of NF-kB (Matta and Chaudhary, 2004). Latent expression of vFLIP makes this protein an attractive candidate for contributing to human tumors. Expression of vFLIP enhances tumorigenicity of mouse B lymphoma cells in immunocompetant mice strains (Djerbi et al., 1999), suggesting a role in human KSHV-induced tumors.

The mitochondrial anti-apoptotic proteins: vBCL-2, vIAP

Both intrinsic and extrinsic apoptotic signaling ultimately merge at mitochondria to initiate membrane depolarization, release of cytochrome c and formation of the apoptosomal proteins required for chromatin condensation and endonucleolytic cleavage, volume contraction and the breakdown and blebbing of membrane structures that result in apoptotic cell death (Danial and Korsmeyer, 2004).

As previously indicated, critical components of this process are the BCL-2 family of proteins (BCL-2 referring to the second B-cell lymphoma related rearrangement protein found (Bakhshi et al., 1985) with the cyclin D1 being “BCL-1”). BCL-2 members have up to four conserved BCL-2 homology (BH) domains and dimerize with each other in the mitochondrial membrane. BH1, BH2 and BH3 domains on antiapoptotic members form a hydrophobic pocket which sequesters proapoptotic BH3-only containing members, such as BID, of the BCL-2 family. Some proapoptotic BCL-2 family members, including BAX and BAK, possess all three BH domains but may have specific activation at the BH3 domain which initiates their proapoptotic activity (Danial and Korsmeyer, 2004).

KSHV and other DNA viruses (Cuconati and White, 2002) encode homologues to the cellular BCL-2 antiapoptic protein (Sarid et al., 1997). vBCL2 encoded by ORF16 was the first KSHV protein to be investigated for its apoptosis-inhibitory properties (Cheng et al., 1997; Sarid et al., 1997) and possesses BH1 and BH2 domains. Solution structure studies suggest structural similarities to BH3 and BH4 domains being present (Huang et al., 2002) allowing the KSHV protein to tightly bind pro-apoptotic Bak and Bax peptides, consistent with two-hybrid heterodimerization studies (Sarid et al., 1997). Whereas cellular BCL-2 can be cleaved by caspase proteolysis and converted to a pro-apoptotic version, KSHV vBCL-2 lacks this cleavage site and escapes cellular regulation (Bellows et al., 2000). Also, as previously indicated, vBCL-2 may serve a specific role in KSHV infected cells since it escapes inactivation by the KSHV vCYC protein which can occur for the cellular BCL-2 (Ojala et al., 2000).

Recent studies also suggest an novel role for viral BCL-2 members in preventing cell death. In addition to apoptosis, autophagy – programmed lysosomal degradation of cytosolic components – plays a critical role in inhibiting intracellular pathogens and initiating CD4 + antigen presentation (Schmid et al., 2006). Liang and colleagues demonstrated that the murine γHV-68 vBCL-2 binds to the autophagy signaling complex composed of UVRAG and Beclin-1 (Liang et al., 2006). vBCL-2 inhibition of autophagy is an attractive mechanism for gammaherpesviruses to escape this innate immune signaling pathway. Thus, vBCL-2 may help KSHV and related viruses escape both apoptotic and autophagic surveillance systems.

vBCL-2 is expressed as an early gene during lytic replication (Sarid et al., 1997; Sun et al., 1999), and presumably delays apoptosis to allow optimal virion production (Cuconati and White, 2002). Immunostaining of KS tissues shows vBCL-2 production in a minority of infected spindle cells of advanced nodular lesions also consistent with a role primarily in delaying lytic apoptosis in vivo (Widmer et al., 2002).

Another KSHV molecule acting as an antiapoptotic factor at the mitochondrial member is the recently investigated viral inhibitor of apoptosis protein (vIAP) encoded by ORF K7 (Feng et al., 2002; Wang et al., 2002). KSHV vIAP possesses a BH2 domain and localizes to mitochondrial membranes where it stabilizes mitochondrial membranes from apoptotic Ca+2 depolarization induced by a variety of agents (Feng et al., 2002). While a BCL-2-like interaction may account for some of the antiapoptotic properties of this protein, vIAP interacts with ubiquillin (also known as PLIC1) which regulates the proteosomal machinery. K7 binding to ubiquillin may enhance polyubiquitin-mediated proteolysis of key apoptotic signaling molecules including IK-B and p53 (Feng et al., 2004). vIAP is expressed during lytic replication, but also can be seen immediately after infection with KSHV suggesting a critical role for this protein in preparing the cell for successful viral invasion (Krishnan et al., 2004).


Further, recent studies suggest that many of these “lytic cycle” proteins are actually activated during latency by transcriptional signaling such as notch. Thus, there is a large array of KSHV nonstructural proteins that may contribute cell transformation, and by extension, to KSHV-related tumorigenesis.

In contrast to the small DNA tumor viruses that have only one, or a few, likely viral oncoproteins, KSHV possesses startlingly large number of nonstructural proteins targeting cellular control pathways that regulate cellular proliferation. Multiple KSHV proteins inhibit cellular controls of the cell cycle. Both LANA1 and vCYC directly target negative cell cycle regulators and bypass normal cellular feedback controls that limit cell proliferation. Similarly, KSHV inhibits intrinsic and extrinsic apoptotic signaling at multiple levels using many different proteins, that include direct targeting of p53 as well as targeting both upstream and downstream signaling pathways to p53.

While it is likely that only a few KSHV proteins principally contribute to oncogenesis, it remains to be determined which proteins this are. Latency-expressed proteins are the leading candidates but recent studies reveal that KSHV genes traditionally thought of as being lytic cycle genes can be induced during viral latency. In addition, paracrine contributions to neoplasia have long been thought to be important for KS tumors adding an additional layer of complexity to KSHV-induced cell transformation. One likely reason for the large number of KSHV proteins targeting cellular control machinery is that they act in different tissues that are infected with the virus. This is most obvious example for this is LANA2 which is not appreciably expressed in KS endothelial cells. Similarly, vIRF1 and K1 may have widespread expression in KS tumors that is not found in cultured PEL cells in the laboratory. Although KSHV appears to encode many more ‘oncoproteins’ than other viruses, this may be more apparent than real. KSHVõs molecular piracy makes identification of regulatory proteins relatively easy; it is possible that additional, functionally-similar proteins will be found in the other herpesviruses as well.

A more salient question is “Why does KSHV dysregulate the cell cycle and control apoptotic signaling?” One explanation is that during lytic replication, KSHV needs to generate a cell environment that can replicate thousands of copies of viral DNA. This view assumes a passive role for the cell during virus replication. It is becoming increasingly clear, however, that lytic virus replication activates host cell defenses that attempt to shutdown the cell cycle or to initiate apoptotic cell death. While the tumor suppressor feedback control machinery is traditionally thought to be a means of preventing spontaneous tumor cell generation, it works extremely well to also limit virus replication (Moore & Chang, 2003). Evidence for the interplay between innate immune signaling and tumor suppressor signaling (Takaoka et al., 2002) makes it increasingly likely that tumor suppressor pathways have evolved for the equally important role of controlling viral replication (Moore & Chang 1998). Seen from this light, KSHV ‘oncoproteins’ may actually be innate immunity evasion proteins that allow the virus to escape from hostile cellular responses to virus infection.


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