Kaposi's sarcoma-associated herpesvirus (KSHV), the most recently discovered oncogenic herpesvirus, is highly associated with a number of AIDS-related malignancies including Kaposi's sarcoma (KS). Although KS is most commonly found in HIV positive patients, KS is also highly prevalence in sub-Saharan Africa and is also a growing problem amongst immuno-suppressed individuals, such as patients undergoing organ transplantation. Like all herpesviruses, KSHV exists in two distinct life cycles: a dormant latent state and a lytic reactivated state. Latent infection of KSHV was largely studied in its tumorigenesis however, clinico-epidemiologic studies suggest that it is this reactivated state that is linked to the subsequent development of KS. Although how the dormant virus is reactivated is still not fully understood, regulator of transcription activation (RTA), a key regulator of the switch from latent to lytic replication, is known to be involved. The major focus in this dissertation will be on brief background to KSHV and discuss how the KSHV virus is reactivated and the role played by the virus-encoded RTA protein in this process.
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Kaposi's sarcoma, the most common cancer in HIV -infected person, was primarily discovered by a Hungarian dermatologist Moritz Kaposi in 1872. He describing the skin lesion in five men in his publication entitle Idiopathisches multiples Pigmentsarkom der Haut (idiopathic multiple pigmented sarcoma of the skin). After two decades another premium dermatologist, Kobner, designated the disease as Kaposi's sarcoma which is now commonly known as classic KS (cited in Antman and Chang, 2000). Over decades of study on the etiology and pathogenesis of Kaposi's sarcoma (KS) has now enlightened us the tumorigenesis of KS, although it is still in the midst of journey today. The identification of causative agents was not intensively study until early 90s when KS was dramatically increased in AIDS patients. This sudden increase in prevalence strongly suggested an involvement of infectious agents in KS development. This agent was first described in 1994 by a research team of Yuan Chang and Patrick Moore at Columbia University, who used representational difference analysis (PCR based techniques) to characterize the DNA sequence of KS biopsies and found that novel Human Î³ herpes virus DNA sequences were constantly present in the KS lesions. This new virus become known as Kaposi's sarcoma-associated herpesvirus (KSHV) or Herpesvirus 8 that is associated with several human cancers including Kaposi's sarcoma, the primary effusion lymphoma (PEL) (Cesarman et al., 1995) and a subset of multicentric Castleman's diseases (Soulier et al., 1995). Successful sequencing of KSHV genome (Russo J.J. et al., 1996) has further sophisticated the knowledge of functions of viral encoded proteins, mechanisms of oncogenesis in molecular, clinical research and potential targets for therapeutic intervention. KSHV, composed with 165Kb DNA sequences which encode up to 90 viral products (Russo J.J. et al., 1996), undergoes two distinguishable viral life cycle; the latent and lytic infection. During infection by KSHV, latent infection being established well before progression to full-blown disease (Martin et al., 1998) and viral DNA resides primarily in endothelial lineage-derived spindle cells (Boshoff et al., 1995). Although it is predominantly in latent cycle, several evidences support that lytic viral replication is also important in KS development. First, the incidence of KS is ten times higher in KSHV seropositive patients who have PBMC (peripheral blood mononuclear cell) viremia than those without virus in the peripheral blood (Engels et al., 2003). Second, treatment of KS risked AIDS patients with ganciclovir, a nucleoside analogue that competitively inhibits herpesviral DNA polymerase proteins and slows the elongation of DNA chains and blocks lytic replication, strikingly reduces the incidence of KS development (Martin et al., 1999). Last, the viral load in peripheral blood mononuclear cells increases with progression to clinical KS (Ambroziak et al., 1995). These findings suggest that reactivation from latency and subsequent lytic replications are important events in KS pathogenesis. Such events would likely represent an important part of the mechanism underlying the association between human immunodeficiency virus infection and KS.
Kaposi's sarcoma can be generally grouped into 4 epidemiological forms. Classic KS are characterized by unusual multifocal neoplasm with dark purple lesions and predominant cell being the spindle cell and this is predominantly affecting the elderly men of Mediterranean, Eastern European and Jewish origins. Prior to the HIV/AIDS era, Kaposi's sarcoma was mainly seen in Sub-Saharan Africans, southern Italy or Mediterranean regions and in immunosuppressed HIV (+) patients or transplant recipients (Ahmed et al., 2001), but rarely (less than 5%) seen in Western countries (Gao, S.J et al., 1996). This raises the hypothesis that development of Kaposi's sarcoma is highly associated with some geographical distribution. However, since the first identification of disseminated form of skin lesions in young homosexual with AIDS in 1981 it is classified as AIDS-related epidemic KS (AKS) (Friedman-Kein et al., 1981). Endemic forms (EKS) was first identified in 1950s and it is more aggressive than classic forms. This is highly prevalence in equatorial zones of Africa and mainly affected to young men and children. In fact, AIDS epidemic has played an important role in the prevalence of KS in Africa. The last type termed iatrogenic KS occurred mainly among immunosuppressive and organ transplant recipients although is not as high as risks seen in HIV infection (Regamey et al., 1998). This suggests that damage in immune system would be predisposing factors for KSHV infection and subsequent KS development. The observation of the geographic variation in incidence of KS suggests that there may be association with host genetic variation. Several studies have claimed the potential contribution of genetic polymorphisms of inflammatory and immune response genes in different types of KS although it is slightly low significant in overall risks. Diplotypes of interleukin-8 receptor-Î² (IL8RB), IL-13 (Brown, E. E. et al., 2006) and certain human leukocyte antigen (HLA) haplotypes (Dorak, M. T. et al., 2005) is suggested to associate with classic KS. Iatrogenic KS is associated with IL6 promoter polymorphism (Gazouli, M. et al., 2004).
Molecular biology of KSHV
KSHV genomic organization and structure
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Like others rhadinoviruses, KSHV genomic organization consists of a central segment of low-GC DNA (L DNA) flanked in High-GC DNA (H DNA) (Russo et al., 1996). KSHV encodes 87 open reading frames (ORFs) and at least 17 microRNAs, 14 of which are co-expressed as a cluster. KSHV DNA is in a linear, double-stranded form in the viral capsid, but following infection, rapid circularization of the viral genome occurs and, like other herpesviruses, KSHV exists as an episome (double-stranded circular DNA) within the host nucleus. KSHV genome consist highly conserved gene block separated by short, interspersed regions containing unique or subfamily specific genes. Conserved ORFs such as (ORF25 for the major capsid protein, ORF9 for the DNA polymerase) usually encode either structural proteins or genes that needed for viral DNA replication and regulation of gene expression. The KSHV genome also contains several unique genes (with a "K" prefix in their names) that are not found in any other rhadinoviruses, including some genes with homologies to interferon regulatory factors (IRFs) (Gao, S.J et al., 1997). KSHV can be classified into four categories based on their viral life cycle expression kinetics; latent genes, immediate-early (IE) genes, early genes, and late genes. Five latency genes have been identified in latent state, includes the kaposin, the v-FLIP, the v-cyclin, latency-associated nuclear antigens (LANA), and the vIRF-2 or LANA-2 (Burysek and Pitha, 2001; Saveliev et al., 2002). The IE genes are made earliest after infection or reactivation from latent to lytic replication. IE genes usually encode proteins for regulatory proteins for genes expression during infection and reactivation. Synthesis of IE genes does not required de nova protein synthesis and also not sensitive to the protein synthesis inhibitor cycloheximide. The most important IE genes in carcinogenesis are ORF50 which encode the expression of replication and transcription activator (RTA), the main regulator for the viral lytic replication programme. Early lytic genes include those encoding viral proteins required for DNA replication or viral gene expression, whereas late lytic genes are those encoding viral structural proteins, such as envelope and capsid proteins, that are required for assembly of viral particles (virions).