In addition to KS, KSHV was found to be associated with two other lymphoproliferative disorders, PEL and multicentric Castleman’s disease (MCD) (Cesarman et al., 1995; Soulier et al., 1995). PEL is a very rare subtype of NHL, predominantly associated with HIV-infected individuals. PEL was first identified as a subset of body cavity-based lymphomas (BCBL), which were subsequently called PELs (Cesarman et al., 1995). This type of lymphoma is distinguished from others as having a distinctive morphology, bridging large cell immunoblastic lymphoma and anaplastic large cell lymphoma. PELs are extremely rare tumors, and estimated to be about 0.13% of all AIDS-related malignancies in AIDS patients in the United States (Mbulaiteye et al., 2002). PELs are unique as they were found to contain KSHV DNA and are most frequently found in male AIDS patients. Most PELs are coinfected with EBV and KSHV and lack c-myc gene rearrangements, and the role of EBV in this type of tumors will be described in a section. MCD, also known as multicentric angiofollicular lymphoid hyperplasia, is a very rare polyclonal B-cell lymphoproliferative disorder with vascular hyperplasia involving multiple lymphoid organs. This disease is both clinically and morphologically heterogeneous, and is defined using clinical and pathological characteristics (Soulier et al., 1995). Unlike KS, where KSHV sequences can be detected in almost all KS samples, the B cells in MCD are usually not infected. In situ hybridization studies showed that the KSHV-infected cells are mainly located in the mantel zone of the follicle and high levels of the viral homologue of the cellular cytokine vIL-6 can be detected, suggesting that uninfected cells are recruited and stimulated to grow in the affected areas (Katano et al., 2000). It is likely that KSHV may be playing an indirect role in the disease.

Unlike most other herpesviruses, KSHV infection does not seem to be widely distributed in most populations. The detection of KSHV infection relies on the presence of antibodies against either lytic and/or latent antigens and varies among the different tests that were used in different seroprevalence studies. There are several different methodologies for the detection of antibodies to KSHV. Most of these assays are based on immunofluorescence antigen (IFA), utilizing B-cell lymphoma cell lines known to be infected with KSHV as the antigen source or based on ELISA with recombinant immunogenic proteins or peptides of KSHV. The performance of these assays can be quite variable, and could account for the differences in seroprevalence reported in different studies (Pellett et al., 2003; Rabkin et al., 1998; Tedeschi et al., 2002). In North America and Northern and Western Europe, KSHV seroprevalence in adult general population or blood donors ranges from 0% to 8% (Challine et al., 2001; de Sanjose et al., 2002; Gambus et al., 2001; Gao et al., 1996b; Goedert et al., 1998; Lennette et al., 1996; Simpson et al., 1996). In these countries, the seroprevalence of KSHV in different risk groups mirrors the incidence of AIDS-KS, with a seroprevalence rate of between 25% and 50% among homosexual men. On the contrary, the reported seroprevalence of KSHV is high in the adult general population in regions of Brazil, French Guiana, the Mediterranean basin, and Central and Southern Africa, where it ranges from 10% to over 80%; these regions are considered endemic for KSHV (Cunha et al., 2005; Freitas et al., 2002; Kazanji et al., 2005; Klaskala et al., 2005; Mayama et al., 1998; Mbulaiteye et al., 2003; Olsen et al., 1998; Plancoulaine et al., 2000, 2004; Wilkinson et al., 1999). Central African countries, like the Republic of Congo, Uganda, and Zambia, also have the highest KSHV infection rates in the world (Gao et al., 1996b). Therefore, KSHV seroprevalence tracks very closely with KS, with the highest infection rate in geographic areas where classic or endemic forms of KS are more common.

The biologic hallmark of the EBV-cell interaction is latency. EBV establishes several latencies on infection of target cells. Three types of latency have been described, each having its own distinct pattern of EBV gene expression. Type I latency is exemplified by Burkitt’s lymphoma (BL) tumors in vivo and earlier passages of cultured cell lines derived from BL biopsies. Epstein-Barr Nuclear Antigen 1 (EBNA-1) and small EBV-encoded, nonpolyadenylated nuclear RNAs (EBER-1 and -2) are expressed in this form of latency. Type II latency is exemplified by NPC and Hodgkin’s disease. EBNA-1, latent membrane protein 1 (LMP-1), LMP2A, and LMP2B proteins, as well as EBERs, are expressed in type II latency. EBV transforms adult primary B cells into continually growing lymphoblastoid cell lines (LCLs) and concomitantly establishes type III latency in vitro. Nine viral proteins are expressed, including six nuclear proteins (EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, and EBNA-LP) and three integral membrane proteins (LMP-1, LMP-2A, and LMP-2B) plus EBERs (Kieff, 1996; Rickinson and Kieff, 1996). Extensive mechanistic studies on EBV transformation have identified several key viral genes that contribute to the viral transformation processes. They are LMP-1, LMP-2, EBNA-1, and EBNA-2.

Extensive studies have led to some insight into the molecular mechanisms underlying the function of LMP-1. LMP-1 is an integral membrane protein with six transmembrane-spanning domains and a long C-terminal domain located in the cytoplasm (Kieff, 1996; Liebowitz et al., 1986). LMP-1 acts as a constitutively active, receptor-like molecule that does not need the binding of a ligand (Gires et al., 1997). The six transmembrane domains mediate oligomerization of LMP-1 molecules in the plasma membrane, a prerequisite for LMP-1 function (Floettmann and Rowe, 1997; Gires et al., 1997). Two regions in the C-terminus of LMP-1 have been shown to initiate signaling processes, the C-terminal activator regions 1 (CTAR-1, amino acids 194-231) and 2 (CTAR-2, amino acids 332-386) (Huen et al., 1995; Mitchell and Sugden, 1995). In a more refined analysis, several kinds of functional domains have been identified. The PXQXT domain is located within the CTAR-1 and is involved in the interaction with tumor necrosis factor receptor (TNFR)-associated factors (TRAFs), and the binding of TRAFs to LMP-1 results in the induction of the NF-κB and AP-1 transcription factors. It is thus apparent that LMP-1 shares functional properties with members of the TNF-receptor superfamily, particularly CD40. Moreover, LMP-1 can partially restore the wildtype phenotype of mice deficient in CD40 (Devergne et al., 1996, 1998; Miller et al., 1997, 1998; Sandberg et al., 1997). LMP-1 also interacts with TNFR-associated death domain protein (TRADD) and receptor-interacting protein (RIP) at the C terminal (Devergne et al., 1998; Floettmann and Rowe, 1997; Izumi et al., 1997, 1999; Izumi and Kieff, 1997; Kaye et al., 1996). Interaction with these two molecules contributes the majority of the NF-κB activity induced by LMP-1. Also, c-Jun N-terminal kinase (JNK) is activated by CTAR-2. The domain for activation is mapped to most C-terminal amino acids and apparently overlaps the TRADD interaction domain. However, whether TRADD and TRAF2 are involved in the activation of JNK is disputed (Eliopoulos and Young, 1998; Eliopoulos et al., 1999; Kilger et al., 1998). In addition, two janus kinase 3 (JAK3) binding sites have been identified between CTAR-1 and CTAR-2. JAK3 binding to the sites is responsible for the activation of STAT-1(Gires et al., 1999). However, some other experimental evidence suggests an alternative mechanism (Brennan et al., 2001; Higuchi et al., 2002; Zhang et al., 2004b). In summary, the hijacking of these cellular signaling pathways by LMP-1 is likely to contribute to the pathogenesis of most EBV-associated disorders through the simultaneous or sequential activation of signals involved in the promotion of cell activation, growth, and survival.

Unlike LMP-1 and EBNA-2, the LMP-2 protein is not essential for B-cell transformation in vitro. Nevertheless, the constant expression of LMP-2 in EBV-carrying memory B cells from healthy individuals suggests that LMP-2 probably plays an important role in viral persistence. LMP-2 in transgenic mice model has shown that LMP-2 provides survival signals that allow immature B cells to progress through developmental checkpoints and prevent cell death. This property may be related to the ability of LMP-2A to activate the serine-threonine kinase Akt. Akt is a multifunctional mediator of phosphatidylinositol 3-kinase (PI3-K) activity. Activation of the pathway results in the constitutive delivery of an antiapoptotic signal. Akt is also involved in the control of B-cell proliferation because chemical inhibition of PI3-K induced growth arrest of EBV-transformed B cells (Brennan et al., 2002).

EBV appears to play a major pathogenetic role in AIDS-associated PCNSL: (1) EBV genome within tumors is present in more than 95% of AIDS patients, but in only 0-20% (probably <5%) of immunocompetent patients. (2) More than half of AIDS PCNSL examined so far expressed at least EBNA-2, LMPs, and EBERs, a pattern referred to as type III latency and closely resembling that seen in transformation of primary B lymphocytes in vitro EBV (Cingolani et al., 2005; Ivers et al., 2004). Expression of type III latency genes leads to a variety of cellular effects, including upregulation of the genes that are involved in transformation, such Bcl-2 and IRF-7, and inactivation of the p53 and Rb tumor suppressor gene products. It is believed that the EBV triggers certain PCNSL in vivo in a process similar to transformation processes of primary B cells in vitro (Pagano, 1999).

At molecular levels, unique sets of cellular genes are expressed in dually infected, but not singly KSHV-infected PELs (Fan et al., 2005). KSHV reduces the expression of EBV EBNA-1 and represses EBV EBNA-2 activation (Krithivas et al., 2000). EBV inhibits KSHV lytic replication, in part, because of a regulatory loop in which KSHV lytic gene induces EBV LMP-1, and LMP-1, in turn, inhibits the lytic gene expression programs of KSHV (Xu et al., 2007). Like EBV EBNA-2, KSHV replication and transcriptional activator (K-RTA) bind to RBP-Jk (Liang et al., 2002), a key cellular target of the EBV latent transforming program (Zimber-Strobl and Strobl, 2001). Also, KSHV induces the expression of CD21, the cellular receptor for EBV, and thus facilitates EBV infection (Chang et al., 2005). All this data suggests that coordinated cellular transformation by the two viruses is a possibility. However, how these two viruses interact and affect each other and the pathobiology of PELs remains to be determined.

Cervical cancer and precancerous lesions (CIN) are now the most common cancer-related affliction affecting women in sub-Saharan Africa and other developing countries in the world. The rates of cervical cancer in Africa are fourfold higher in than in North America and Europe.