1. Exposure Data

1.1. Taxonomy, structure, and biology

1.1.1. Taxonomy

First detected by Chang et al. (1994) in Kaposi sarcomas associated with the acquired immune deficiency syndrome (AIDS) (see IARC, 1996) by representational difference analysis, this virus was termed Kaposi-sarcoma-associated herpesvirus, KSHV. KSHV is also associated with primary effusion lymphoma and some cases of multicentric Castleman disease (see Section 2). In keeping with the systematic nomenclature adopted for all human herpesviruses, the formal designation human herpesvirus 8 (HHV-8) was proposed by the herpesvirus subcommittee of the International Committee on the Taxonomy of Viruses. In this Monograph, the term KSHV is used throughout.

On the basis of phylogenetic analyses (Moore et al., 1996a; Russo et al., 1996), KSHV is a gamma-2 herpesvirus (rhadinovirus), and represents the first ‘human’ member of this group. There are many more gamma-2 herpesvirus species in old and new world non-human primates.

1.1.2. Structure of the virion

KSHV has the typical morphological characteristics of a herpesvirus (Fig. 1.1; Arvanitakis et al., 1996; Renne et al., 1996a; Orenstein et al., 1997) with 100–150 nm particles surrounded by a lipid envelope, and an electron-dense central core (Renne et al., 1996b). Cryo-electron microscopy (Cryo-EM) and Cryo-EM tomography studies suggest that KSHV capsomers are hexamers and pentamers of the major capsid protein (encoded by the open reading frame [ORF] 25), with the small capsid protein (encoded by ORF 65), binding around the tips of both hexons and pentons (Trus et al., 2001; Deng et al., 2008).

Fig. 1.1

Electron microscopic view of KSHV capsids in a cross-section of a spleen Kaposi sarcoma

1.1.3 Structure of the viral genome

KSHV has a double-stranded DNA genome. The genomic structure of the virus (Russo et al., 1996; Neipel et al., 1997a) is similar to that of other primate rhadinoviruses, e.g. Herpesvirus saimiri (Albrecht et al., 1992) or Rhesus Rhadinovirus (Searles et al., 1999; Alexander et al., 2000), with a single, contiguous 140.5-kb-long unique region containing all the identified viral genes (Russo et al., 1996; Neipel et al., 1997a; Fig. 1.2). This region is flanked on either side by a terminal-repeat (TR) region composed of a variable number of repeats of 801-bp length with a high G:C (84.5%) content. Due to the variable number of repeat subunits (some of the repeat subunits may be truncated), the overall length of the TR region varies, and with it, the overall size of the KSHV genome. The latter has been calculated to be approximately 165 kb on the basis of studies of the viral genome from productive primary effusion lymphoma cells (Arvanitakis et al., 1996; Renne et al., 1996b), and mapping of the whole genome (Russo et al., 1996).

Fig. 1.2

Annotated long unique region and terminal repeats of the KSHV genome

(a) Terminal-repeat region

The TR region is a conserved feature of herpesviruses, and is involved in the packaging of the viral DNA into new virions during the lytic cycle of replication. Depending on the viral strain, KSHV has approximately 20–30 TR units. A particular feature of the KSHV TR unit is that it contains two binding sites for the KSHV latent nuclear antigen (LANA) and the latent (episomal) origin of replication (Garber et al., 2001; Hu et al., 2002). By binding to multiple TR subunits, LANA tethers circular viral episomes to mitotic chromosomes during mitosis (Ballestas et al., 1999; Barbera et al., 2006). LANA is also required for the replication of viral episomes by recruiting a range of cellular factors involved in DNA replication (see Section 4.1). Currently, the TR region is not known to contain any protein-coding ORFs in contrast to, for example, EBV (Longnecker & Neipel, 2007).

(b) Long unique region

The KSHV 140.5-kb long unique region encodes approximately 90 predicted ORFs (Russo et al., 1996; Neipel et al., 1997a; Fig. 1.2). The ORFs were named according to the corresponding herpesvirus saimiri genes with which they share a significant level of sequence similarity. Unique genes that are not homologous with herpesvirus saimiri have a K prefix. The long unique region has blocks of genes conserved among all subfamilies of herpesviruses (Chee et al., 1990), which include genes that encode herpesvirus structural proteins and replication enzymes. Between the conserved herpesvirus gene blocks lie blocks of genes that are either found in rhadinoviruses or are unique to KSHV (Russo et al., 1996). Several of these share significant sequence similarity with cellular genes, and were presumably carried away at some point during the evolution of these viruses.

The long unique region also contains genes for untranslated RNAs. Among these is the PAN/nut-1 transcript, a nuclear untranslated RNA, whose function is not yet clear (Sun et al., 1996; Zhong & Ganem, 1997). In addition, KSHV encodes at least 12 microRNAs, which are generated from one transcript, and located downstream of the ORFK13/vFLIP (Cai et al., 2005; Samols et al., 2005).

The probable function of these genes in the virus life cycle and tumour formation is discussed in Section 4.1.

1.1.4. Host range and tropism

Humans are the natural hosts for KSHV. Epidemiological studies indicate that KSHV is more prevalent in subSaharan Africa, several countries of southern Europe, the North African Mediterranean coast, and several countries of South America compared to northern Europe, North America, and Asia (see Section 1.2).

In vivo, KSHV has been detected in endothelial and spindle cells of Kaposi sarcoma lesions, in circulating endothelial cells, primary effusion lymphoma cells, B cells, macrophages, dendritic cells, oropharynx and prostatic glandular epithelium and keratinocytes (Ambroziak et al., 1995; Boshoff et al., 1995; Cesarman et al., 1995a; Moore & Chang, 1995; Corbellino et al., 1996; Li et al., 1996; Sirianni et al., 1997; Staskus et al., 1997; Stürzl et al., 1997; Reed et al., 1998; Pauk et al., 2000).

Of the cell types targeted by KSHV in vivo, primary endothelial cells of different differentiation (vascular, lymphatic, endothelial precursor cells), monocytes, dendritic cells, fibroblasts, epithelial cells and keratinocytes can be infected in vitro (Renne et al., 1998; Blackbourn et al., 2000; Cerimele et al., 2000; Wang et al., 2004a; Rappocciolo et al., 2006). It was shown that B cells can only be infected in vitro at a specific differentiation stage (Rappocciolo et al., 2006, 2008).

1.1.5. Viral life cycle

KSHV, like all herpesviruses, can establish lifelong latent infections in their human host. Latenly infected cells provide a perpetual reservoir from which progeny viruses can be amplified for dissemination within the host and transmission between hosts. The peripheral blood CD19-positive B cells have been identified as a long-term latency reservoir for KSHV; other cells such as endothelial cells may also be a site for KSHV latency, but they do not appear to provide a long-term latent reservoir for the virus. Nonetheless, infected dermal endothelium spindle cells may release progeny virus that can subsequently infect local keratinocytes and the eccrine epithelium in the tumour. Lytic reactivation from latently KSHV-infected cells that results in the release of progeny virions is a critical pathogenic step in multiple human diseases. In immunocompetent KSHV carriers, the immune system plays an essential role in tempering lytic reactivation of the virus (see Lukac & Yuan, 2007 for a detailed review).

2. Cancer in Humans

3. Cancer in Experimental Animals

In this Volume, the Working Group decided not to include a separate section on “Cancer in Experimental Animals” in the Monographs on viruses but rather to include description of such studies under Section 4 (below). The reasoning for this decision is explained in the General Remarks.

4. Other Relevant Data

4.2. Biochemical and biological properties of KSHV proteins

Several latent or lytic viral proteins are involved in the carcinogenesis process of KSHV (see Table 4.1).

Table 4.1

Biochemical and biological properties of KSHV proteins .

Five KSHV proteins (K1/VIP, vGPCR, vIRF-1, Kaposin A, LANA) have been reported to have transforming properties in classical transformation assays, others (vCYC, LANA, KbZIP) have been shown to affect cell-cycle regulation or the survival of tumour cells in vivo or in vitro (vFLIP, vIL6, vIRF-3). Because only some of these proteins are expressed during latency and in the majority of tumour cells, not only ‘direct’ transformations (as in classical models of virus-mediated cellular transformation) but also indirect (paracrine) effects are thought to play a role in KSHV-mediated oncogenesis (Ganem, 2007).

4.2.1. Latent KSHV proteins

(a) LANA/ORF 73

LANA, encoded by ORF 73, is expressed during latency and represents the most consistently detected viral protein in KSHV-associated tumour cells (Rainbow et al., 1997; Dupin et al., 1999; Katano et al., 2000; Parravicini et al., 2000). LANA is necessary for replicating the episomal viral DNA; it binds to the latent origin of replication in the TR subunits of the viral genome, and works by recruiting a large variety of cellular interaction partners, among them components of the chromosomal replication machinery such as origin recognition complexes (ORCs), but also cellular proteins linked to transcriptional regulation or proliferation control (see Table 4.1; reviewed in Verma et al., 2007).

Of relevance to a possible direct role of LANA in oncogenesis are the observations that LANA: (i) inactivates p53-dependent transcriptional activation (Friborg et al., 1999); (ii) interacts with pRB and enhances oncogenic ras-mediated transformation of rodent fibroblasts (Radkov et al., 2000); (iii) absorbs GSK-3β and thereby reduces the phosphorylation of, thus stabilizing, β-catenin (Fujimuro et al., 2003); (iv) interacts with Brd2/RING3, a chromatin-binding protein and a lymphomagenic member of the BET protein family (Platt et al., 1999; Viejo-Borbolla et al., 2005); (v) causes B-cell hyperplasia and B-cell lymphoma when expressed in transgenic mice (Fakhari et al., 2006).

(b) vCYC/ORF 72

In-situ hybridization studies indicate that the KSHV CYC/ORF 72 gene is expressed in the majority of tumour cells in vivo (Davis et al., 1997), in keeping with its classification as a latent gene. v-CYC represents another candidate KSHV oncoprotein because of its homology to the human Cyclin-D/Prad oncoprotein. In general, cyclin-D proteins (D₁, D₂, D₃) associate with specific cyclin-dependent kinases (CDKs), and these complexes phosphorylate pRB family members (reviewed in Sherr, 1996). An oncogenic cyclin-D homologue is also present in other gammaherpesviruses (reviewed in Neipel et al., 1997). Ectopic expression of the murine herpesvirus 68 (MHV 68) cyclin in T cells causes T-cell lymphomas in transgenic mice (van Dyk et al., 1999).

The mechanism of transformation by KSHV vCYC is most likely novel and unique, because it phosphorylates pRb but, unexpectedly, also histone H1, p27^KIP1, and Bcl-2 (Chang et al., 1996; Godden-Kent et al., 1997; Li et al., 1997; Ojala et al., 2000). Unlike human cyclin-D, vCYC/CDK6-mediated phosphorylation of pRB is resistant to inhibition by the cyclin-dependent kinase-inhibitors (CDKIs) p16^INK4, p21^CIP1, and p27^KIP1 (Swanton et al., 1997). Moreover, vCYC/CDK6 induces the degradation of p27^KIP1 (Ellis et al., 1999; Mann et al., 1999).

(c) vFLIP/ORF 71

vFLIP/ORF 71 is transcribed from the LANA promoter, and translated from an internal ribosome entry site located within the v-cyclin coding region (Grundhoff & Ganem, 2001; Low et al., 2001). It is therefore thought to be expressed during latency and in all tumour cells. The vFLIP protein is an adhesion molecule, a homologue of cellular FLICE (caspase-8)-inhibitory protein (FLIP) (Hu et al., 1997). It inhibits CD95/FAS-induced apoptosis in vitro by blocking caspase-3, -8 and -9 (Djerbi et al., 1999).

vFLIP directly binds IKKγ and TRAF2; this leads to a constitutive activation of NF-κB signalling (Field et al., 2003; Guasparri et al., 2006). In addition, vFLIP induces MHC-I expression through NF-κB in KSHV-infected lymphatic endothelial cells (Lagos et al., 2007), which underscores the physiological importance of the vFLIP–NF-κB interaction. Moreover, vFLIP transgenic mice develop lymphoma (Chugh et al., 2005). Eliminating either vFLIP or NF-κB activity from primary effusion lymphoma cells induces apoptosis (Keller et al., 2000; Guasparri et al., 2004), demonstrating that this pathway is essential for lymphomagenesis.

(d) Kaposin A/ORF K12

The many transcripts spanning the predicted K12 ORF (originally called T0.7) are translated in different reading frames, giving rise to the proteins kaposin A, B, C (Zhong et al., 1996; Sadler et al., 1999). In addition, a long transcript extending through ORF K12 represents the precursor RNA for the KSHV microRNAs (Cai et al., 2005; Pfeffer et al., 2005; Samols et al., 2005). One of these microRNAs, miRK-10, is located within the kaposin A sequence. These transcripts are expressed in all Kaposi sarcoma spindle cells (Staskus et al., 1997; Stürzl et al., 1997), and increase after activation of the lytic replication cycle.

Muralidhar et al. (1998) reported that transfection of the kaposin A reading frame into Rat-3 cells induced focus formation, and that these cell lines were tumorigenic in nude mice. There is some discussion as to whether this is due to the kaposin A protein or the miR-K10 located within its sequence. Kaposin A interacts directly with Cytohesin-1, a guanine nucleotide exchange factor for ARF GTPases, and a regulator of integrin-mediated cell adhesion. It was shown that the transformed cellular phenotype induced by Kaposin A in tissue culture could be reversed by a functionally dead Cytohesin-1 mutant (Kliche et al., 2001).

(e) vIRF-3/LANA-2

vIRF-3, one of the viral homologues of interferon regulatory factors, is constitutively expressed in latently KSHV-infected cells, and its expression appears to be tissue specific. vIRF-3 is indeed detected in nearly all primary effusion lymphoma cells and KSHV-associated Castleman disease cells (both of B-lymphocyte origin), but is not expressed in Kaposi sarcoma tumours (endothelial origin) (Rivas et al., 2001).

vIRF-3 binds to and antagonizes p53, and affects the regulation of the interferon response (see Table 4.1).

Knockdown of vIRF-3 in primary effusion lymphoma cells has been shown to induce apoptosis, suggesting that vIRF-3 is required for the survival of KHSV-infected B cells (Wies et al., 2008).

4.2.2. Lytic KSHV proteins

(a) K1/VIP (variable, ITAM-containing protein)

K1/VIP is a viral type I transmembrane protein, featuring two hypervariable domains in its extracellular region, and an immunoglobulin transactivation motif (ITAM) in its C-terminal, cytoplasmic region (Lee et al., 1998b). The K1 protein is expressed during the lytic (productive) replication cycle (Jenner et al., 2001; Paulose-Murphy et al., 2001; Nakamura et al., 2003). Wang et al. (2006) reported that, while expression of K1 is not a consistent feature of Kaposi sarcoma, some Kaposi sarcoma biopsies show a marked K1-expression both at the transcript and protein level. K1-expression was also documented by immunohistochemistry on a small subpopulation of mantle zone lymphocytes of KSHV-positive multicentric Castleman disease, and in primary effusion lymphoma cell lines (Lee et al., 2003).

Lee et al. (1998a) showed that transfection of a K1-expression vector into rodent fibroblasts induced focus formation, and that K1-transfectants induced lymphoma in the common marmoset. Prakash et al. (2002) reported the emergence of sarcomatoid tumours and plasmablastic lymphoma in transgenic mice expressing the K1 protein under the control of an SV40 promoter. These mice showed an increased expression of bFGF; in transgenic B cells, a constitutive activation of NF-κB and increased c-Lyn activity was noted. Wang et al. (2006) showed that retroviral transduction of primary endothelial cells extended their life span.

K1 activates several intracellular signalling cascades leading to increased Ca-influx, increased phosphorylation of Syk, Vav, Cbl, and the p85 subunit of PI3K, increased NF-κB activity, and activation of NFAT and AP1 (Lee et al., 1998b; Lagunoff et al., 1999, 2001). The activation of PI3K leads to the activation of AKT by K1 (Tomlinson & Damania, 2004). K1 induces the expression of angiogenic cytokines, including vascular endothelial growth factor (VEGF), and may therefore play a paracrine role in the pathogenesis of Kaposi sarcoma or primary effusion lymphoma (Wang et al., 2004a, 2006).

(b) vIRF-1/ORF K9

vIRF-1 belongs to a group of four viral homologues of interferon regulatory factors (Russo et al., 1996; Cunningham et al., 2003). Stable vIRF-1 transfectants in murine NIH 3T3 cells show signs of transformation (loss of contact inhibition, growth in soft agar), and cause tumours in nude mice (Gao et al., 1997). The main function of vIRF-1 appears to be the inhibition of interferon-β-regulated genes such as p21^CIP1 (Gao et al., 1997); it also inhibits the induction phase of the interferon response by binding to cellular IRFs (IRF-3, IRF-7), and to the transcriptional co-activators p300 and CBP, and inhibits the formation of functional IRF-3/CBP/p300 complexes and the induction of interferon β transcription (Gao et al., 1997; Burýsek et al., 1999; Seo et al., 2000; Lin et al., 2001). Unlike cellular IRFs, vIRF-1 does not bind directly to cellular DNA.

vIRF-1 is expressed during the lytic (productive) replication in tissue culture and is directly transactivated by K-RTA, the central regulator of the viral lytic programme (Gao et al., 1997; Chen et al., 2000).

(c) vGPCR /ORF 74

ORF 74 encodes a homologue of a G-protein-coupled chemokine receptor, and is constitutively active (reviewed in Nicholas, 2007). It activates a broad range of signalling pathways, including MEK/Erk, JNK, p38, Akt, NFAT, CREB, NF-κB, AP-1, and HIF-1α; these are relevant to the promotion of cell proliferation, cell survival, and angiogenic responses via cytokine gene induction (reviewed in Nicholas, 2007; Hartmann, 2008). Although constitutive, the activity of vGPCR can be modulated both positively and negatively by several cellular chemokines (Groα, IL8, IP-10, SDF-1α), and one viral (vCCL-2) chemokine (reviewed in Hartmann, 2008).

Multiple lines of evidence point to a role of vGPCR in KSHV-induced neoplasia, in particular Kaposi sarcoma. Early studies showed the proliferation-enhancing, constitutive signalling, and transforming properties of vGPCR (Arvanitakis et al., 1997; Bais et al., 1998). Subsequently, vGPCR was shown to cause Kaposi-sarcoma-like tumours in transgenic mice (Yang et al., 2000). In this model, vGPCR was only expressed in a few scattered cells, consistent with a paracrine model involving secretion of angiogenic cytokines (Holst et al., 2001; Guo et al., 2003; Montaner et al., 2003).

In a xenograft model, vGPCR involving a KSHV-transfected murine endothelial cell line was found to be required for tumorigenicity (Mutlu et al., 2007). The relevance of these results to KSHV-associated tumours in humans remains to be determined.

4.2.3 Genomic instability

Evidence of genomic instability has been noted in primary effusion lymphoma cells (microsatellite instability, chromosomal imbalances) (Gaidano et al., 1997; Nair et al., 2006), and late Kaposi sarcoma (Pyakurel et al., 2006). Experimentally, genomic instability has been noted in KSHV-infected primary endothelial cells (Pan et al., 2004), as well as in cell lines stably transfected with LANA (Si & Robertson, 2006), and vCYC-transgenic mice (Verschuren et al., 2004). Abnormal chromosome segregation in KSHV-infected cells was shown to be the consequence of nucleophosmin (NPM1) phosphorylation by CDK6 in concert with vCYC (Cuomo et al., 2008).

4.2.4 DNA-damage response

Transduction of vCYC into primary endothelial cells by a retroviral vector induces a DNA damage response, resulting in the increased phosphorylation of γH2AX (a variant form of histone H2A), which is an early response to DNA double-strand breaks. Increase of γH2AX phosphorylation was also shown in KSHV-infected primary endothelial cells, albeit only after 2 weeks of culture (in spite of vCYC being expressed early on) (Koopal et al., 2007). Other KSHV proteins might therefore interfere with the triggering of the DNA-damage response.

Shin et al. (2006) reported that vIRF-1 prevents the DNA-damage response and γH2AX and p53 phosphorylation by binding to and inhibiting ATM kinase, thereby promoting p53 turnover. As noted above, vIRF-1 and LANA interact with p53 and antagonize the transcription of p53-dependent cellular genes, including p21^CIP1 (Gao et al., 1997; Friborg et al., 1999). In KSHV-infected primary effusion lymphoma cells, vIRF-3 also binds to p53 and inhibits the activation of the p53 promoter (Rivas et al., 2001). In primary effusion lymphoma cells, LANA, p53 and Hdm2 form a trimeric complex (Sarek et al., 2007), and the restoration of the p53 function by treatment with an inhibitor of the p53-Hdm2 interaction – Nutlin-3a – induces apoptosis in primary effusion lymphoma cells (Petre et al., 2007; Sarek et al., 2007).

Most reports have concluded that the inhibition of p53-activated cellular genes by LANA, vIRF-1, and vIRF-3 involves other mechanisms than the degradation or increased turnover of p53. However, one report showed that the recruitment of the Cul5-Elongin BC E3 ligase complex by LANA resulted in the degradation of p53 (Cai et al., 2006).

4.2.5. Cell proliferation and differentiation

KSHV-infected primary endothelial cells undergo spindle cell formation, which express markers of the lymphatic endothelium. Gene expression array studies have shown that KSHV can alter the transcriptome profile of vascular endothelial cells towards a profile that is typical for lymphatic endothelial cells (Carroll et al., 2004; Hong et al., 2004; Wang et al., 2004b). This involves the activation of Prox-1, a transcription factor determining lymphatic endothelial cell differentiation, followed by the increased expression of podoplanin and VEGFR-3 – markers for the lymphatic endothelial cell lineage (Carroll et al., 2004; Hong et al., 2004). The signalling pathways gp130 (the β-chain of the IL6 receptor used by vIL6) as well as PI3K/Akt and JAK2/STAT3 have been reported to be involved in the induction of Prox-1 in KSHV-infected endothelial cells (Morris et al., 2008).

These data raise the possibility that KSHV infects blood or circulating endothelial cells, and drives them to differentiate into the lymphatic endothelium as they become spindle cells. This may be of major importance to Kaposi sarcoma tumour formation (Morris et al., 2008).

The adoption of a spindle morphology in KSHV-infected cells is thought to be due to vFLIP, a homologue of cellular FLIPs, and potent NF-κB inducer; vFLIP is expressed in latently infected endothelial cells, and NF-κB activation appears to be required for the formation of spindle cells (Grossmann et al., 2006; Sun et al., 2006). vFLIP is also required essentially for primary effusion lymphoma cell survival (see Section 4.2.1).

The viral IL6 homologue, vIL6, is expressed in vivo in a subpopulation of primary effusion lymphoma cells and in many KSHV-infected B cells in multicentric Castleman disease lymphoid follicles (Moore et al., 1996c; Katano et al., 2000; Parravicini et al., 2000). It induces proliferation, angiogenesis, and haematopoesis in IL6-dependent cell lineages (Burger et al., 1998; Aoki et al., 1999; Hoischen et al., 2000), and serves as an essential autocrine factor in primary effusion lymphoma cell lines (Jones et al., 1999). It also induces VEGF, which has been implicated in the pathogenesis of primary effusion lymphoma and of Kaposi sarcoma (Aoki & Tosato, 1999). A single-chain antibody to vIL6, blocking its interaction with the IL6 receptor complex, was found to inhibit the proliferation of a primary effusion lymphoma cell line and to inhibit vIL6-induced STAT 3 phosphorylation in vIL6-transfected cells (Kovaleva et al., 2006). Therefore, vIL6 may contribute to primary effusion lymphoma cell proliferation and to the angiogenesis noted in patients with this lymphoma.

Also, the viral D-type cyclin homologue vCYC and LANA each contribute to cell proliferation (see Section 4.2.1)

One of the viral latent transcripts in primary effusion lymophoma cells, miRNA-K12–11, has been found to target the same cellular microRNAs as miRNA-155, a cellular microRNA regulating the germinal centre reaction during B-cell maturation (Gottwein et al., 2007; Skalsky et al., 2007; Thai et al., 2007). Both miRNA-K12-11 and miR-155 downregulate several pro-apoptotic cellular genes (see Table 4.2). miRNA-K12–11 may therefore be involved in blocking terminal B-cell differentiation that contributes to the plasmablastic phenotype of primary effusion lymphoma cells or play a role in the protection of primary effusion lymphoma cells against apoptosis.

Table 4.2

Mode of action of KSHV proteins involved in the protection against apoptosis.

These findings highlight how KSHV can affect the differentiation of endothelial cells and of B cells.

vIRF3, an interferon regulation factor homologue, is required for primary effusion lymphoma cell survival (Wies et al., 2008).

Ablation of the human cytokines IL-6, IL-10, and VEGF or of VEGFR inhibits the growth of primary effusion lymphoma and Kaposi sarcoma (Masood et al., 1997; Nakamura et al., 1997; Aoki & Tosato, 1999; Arora et al., 1999; Jones et al., 1999; Sin et al., 2007). IFN-α inhibits KSHV reactivation and Kaposi sarcoma tumour growth (Krown et al., 1986; Chang et al., 2000).

4.2.6. Apoptosis

Several KSHV proteins have been shown to protect against apoptosis when transfected individually. Among them are some of the proteins already discussed above, as well as a viral homologue of cellular Bcl2. Table 4.2 shows a summary of their mode of actions.

4.6. Transgenic mice models

An alternative approach to infection studies is to use transgenic mice where individual KSHV proteins are expressed in the hope of replicating selected aspects of KSHV pathogenesis. There are some limitations to single transgenic models. Whereas lymphoproliferative lesions and lymphomas in mice are easily classified on the basis of histology and marker–gene expression, this is not the case for endothelial cell tumours. They are referred to as Kaposi-sarcoma-like lesions, but can easily be mistaken for fibrosarcomas (Table 4.3).

Table 4.3

Transgenics for modelling KSHV-associated cancers.

4.6.1. Transgenic mice for KSHV latent genes

(a) LANA/ORF 73

The KSHV latent promoter (LANAp) showed B-cell lineage specificity in transgenic mice (Jeong et al., 2002). KSHV LANA expression in transgenic mice resulted in 100% B-cell hyperplasias and lymphomas at about twice the rate of background in the C57/BL6 strain of mice (Fakhari et al., 2006).

(b) vCYC/ORF 72

Whereas vCYC single transgenic mice did not develop tumours, lymphomas developed rapidly in a p53-null background (Verschuren et al., 2002, 2004). [The Working Group noted that, presumably, loss of p53 counteracted the pro-apoptotic signals that are associated with forced vCYC expression.]

(c) vFLIP/ORF 71

• The vFLIP transgenic mice exhibited an increased incidence of lymphoma (Chugh et al., 2005).

4.6.2. Transgenic mice for KSHV lytic genes

(a) vGPCR/ORF 74.

vGPCR transgenic mice activated the same signalling pathways as predicted from human culture studies, and exhibited Kaposi-sarcoma-like lesions (Yang et al., 2000; Holst et al., 2001; Guo et al., 2003; Montaner et al., 2003; Jensen et al., 2005; Grisotto et al., 2006). Tumour formation required the chemokine binding as well as the constitutive signalling activities of vGPCR (Holst et al., 2001). vGPCR was required for lesion initiation, though it was not essential once a fully malignant tumour had formed (Grisotto et al., 2006).

(b) K1/VIP

K1 transgenic mice also exhibited Kaposi-sarcoma-like lesions and lymphomas (Prakash et al., 2002, 2005).

5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of KSHV. KSHV causes Kaposi sarcoma and primary effusion lymphoma. Also, a positive association has been observed between exposure to KSHV and multicentric Castleman disease.

For multiple myeloma, there is evidence suggesting lack of carcinogenicity.

KSHV is carcinogenic to humans (Group 1).

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