Molecular biology of Kaposi's sarcoma-associated herpesvirus and related oncogenesis

Abstract

Kaposi's Sarcoma-associated Herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the most recently identified human tumor virus,and is associated with the pathogenesis of Kaposi's sarcoma and two lymphoproliferative disorders known to occur frequently in AIDS patients-primary effusion lymphoma and multicentric Castleman disease. In the 15 years since its discovery, intense studies have demonstrated an etiologic role for KSHV in the development of these malignancies. Here, we review the recent advances linked to understanding KSHV latent and lytic life cycle and the molecular mechanisms of KSHV-mediated oncogenesis in terms of transformation, cell signaling, cell growth and survival, angiogenesis, immune invasion and response to microenvironmental stress, and highlight the potential therapeutic targets for blocking KSHV tumorigenesis.

FIGURE 1

A schematic of the KSHV genome consisting of 145 kb long unique, gene-coding region flanked with terminal repeat units. The coding regions contain over 90 open reading frames (ORFs; Russo et al., 1996). The gene-encoded proteins are labeled in the bottom from left to right. ORFs unique to the KSHV are given the prefix K. The miRNA cluster encoding for 12 microRNAs (yellow) is located between K12 (Kaposin) and ORF71 (vFLIP). The blocks representing the ORFs are also labeled in color according to gene class [latent, immediate early (IE), early and late lytic, and unclassified] (based on previous reviews of Coscoy, 2007; Moore and Chang, 2001). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this chapter.)

FIGURE 2

KSHV primary infection and the cell signaling pathways targeted. Infection is initiated by cell fusion or endocytosis. For cell fusion, KSHV fuses with the plasma membrane by gB, gH, gL, gM, gN, and gpK8.1A, then release of virus particles to the cell plasma. For endocytosis, KSHV binds to the cell surface via interactions with heparan sulfate (HS) followed by temporal interactions with integrins and xCT (CD98) molecules, then formation of endocytic vesicles, virus entry, movement in the cytoplasm, release of virus particles, delivery into the nucleus by dynein along the microtubule. Viral gene expression interferes with the cellular signaling pathways such as MAPK, JAK–STAT, Notch, HIF, Wnt, and miRNA, consequently reprograms host cell gene expression.

FIGURE 3

Putative mechanisms of KSHV-mediated regulation of angiogenesis, cell growth and survival, and immune evasion. Cell cycle progression in G1 is controlled by cyclin D/Cdk4/6 complexes which phophorylates Rb. Phosphorylation of Rb leads to Rb inactivation and release transcription factor E2F and transcription of S-phase genes, like Cyclin E and A (Malumbres and Barbacid, 2005). Additionally, p53-mediated Cdk2 and Bax activation and Fas-mediated Caspase activation individually induces cell-cycle arrest and apoptosis. In the latently infected cells, KSHV-encoded latent antigens (green) like LANA and vCyclin drive cell proliferation by targeting two cell-cycle checkpoints: (1) Inactivate Rb to release E2F; and (2) Block p53/p27^Kip1-mediated cell-cycle arrest (Cai et al., 2006a,b; Friborg et al., 1999; Jarviluoma et al., 2006; Mann et al., 1999). Meanwhile, LANA cooperates with vFLIP to block Caspase and Bax-mediated apoptosis (Sarid et al., 1999). However, in a small amount of lytically infected cells, KSHV encodes some early lytic proteins (orange) like vGPCR vIRF and MIR1/2 or miRNA which dysregulate immune system to produce certain cytokines and help viral infection by angiogenesis and inflammation (Wang et al., 2004).

FIGURE 4

Microenvironmental stress promotes the development of KSHV-mediated malignancy. (A) Proliferation of KSHV-infected tumor cells initiates the formation of hypoxia microenvironment; (B) Hypoxic stress induces cell selection by apoptosis and mutation and increases HIFα and VEGF levels; meanwhile, (C) Oxidative stress caused by reoxygenation or overproduction of ROS also induces similar response as hypoxic stress, and thereby (D) selects the survival of malignant tumor cells to promote angiogenesis and tumor progression. On the other hand, (E) the microenvironmental stresses reactivate KSHV from latent infection to produce new virion particles and help viral primary infection.