Introduction

Kaposi’s Sarcoma-Associated Herpesvirus (KSHV; also known as human herpesvirus 8 [HHV8]) is the etiologic agent of Kaposi’s sarcoma (KS), the most common AIDS-related malignancy. KSHV is also associated with primary effusion lymphoma (PEL; also known as body cavity-based lymphoma [BCBL]), and a subset of multicentric Castleman’s disease. The sequence analysis of the KSHV genome suggests that this virus is a gamma-herpesvirus related to herpesvirus saimiri (HVS) belonging to the genus Rhadinovirus. It is also related to Epstein-Barr virus (EBV) and equine herpesvirus 2. (Review by Schulz 2000)

The complete sequence of KSHV (GenBank accession numbers U75698 and U93872) provided a great deal of information from which many open reading frames (ORFs) were predicted and the possible function of some ORFs were suggested (Russo et al, 1996). It was shown that a large portion of the KSHV genome represented by several blocks of genes is conserved among gamma-herpesviruses. These genes mainly encode viral replication and structural proteins. Between the conserved gene blocks, there are clusters of unique genes. At present, there are about two dozen of such genes unique to KSHV, designated K1 to K15. The most striking features of these unique KSHV genes are that most of them are found to share homology to known cellular genes.

With the progress of studies on transcript mapping, more information regarding the gene expression of KSHV genome has become available and additional gene products have been recognized. Examples of these newly recognized open reading frames are K8 (a bZip protein), K8.1 (a glycoprotein) and K10.1 (latent nuclear antigen-2). These open reading frames were not identified in the primary sequence analysis of the KSHV genome because they are encoded by spliced mRNAs. It is assured that when more extensive and detailed transcription studies are completed, more new genes and gene products will be recognized.

Studies on KSHV transcription have revealed many interesting features of viral gene expression. First of all, many genes on the KSHV genome make use of alternative, temporally regulated splicing to access different protein coding domains from the same mRNA precursor (for example, 5.4 kb LANA (ORF 73) and 1.7 kb ORF 71/72 mRNAs; three splicing variants of K8). To date, it appears that KSHV uses mRNA splicing more than any other herpesvirus. In contrast to Herpes Simplex virus type 1 where only four open reading frames (ICP0, ICP22, ICP47 and UL15) have been shown to yield spliced mRNAs, at least 15 KSHV genes have been found to be regulated at mRNA splicing level. Second, significant numbers of KSHV mRNAs were found polycistronic because there are relatively few polyadenylation signals (e.g. transcripts for ORF50/K8/K8.1, K4.2/K4.1/K4, and ORF73/72/71), but usually only the 5’ proximal ORF is translated. The latter ORFs are expressed through one of the following mechanisms: (i) expression using a different transcriptional start site (e.g., K8, Lin et al, 1999); (ii) transportation to the 5’ proximal position by a splicing (e.g., ORF72, Dittmer et al, 1998); (iii) translation via an internal ribosome entry site (e.g. ORF71 (vFLIP), Talbot 2000, personal communication).

As a gamma-herpesvirus, KSHV characteristically establishes latent infection in lymphoid cells. In latently infected cells, KSHV expresses a limited number of genes, which are referred to as latent genes. Five KSHV latent genes were identified, and they encode v-cyclin (ORF 72), latency-associated nuclear antigen (LANA; ORF 73), v-FLIP (ORF 71), kaposin (K12) and K10.1 (LANA-2) (Rainbow et al, 1997; Kedes et al, 1997; Dittmer et al, 1998; Sadler et al, 1999; Sarid et al., 1999). When latency is disrupted, KSHV switches to lytic life cycle, in which the viral genome expresses its lytic genes in a temporal and sequential order. A few viral genes are expressed independently of de novo protein synthesis, and are classified as immediate-early genes. Immediate-early (IE) genes usually encode regulatory proteins, which are required for subsequent viral gene expression. Early genes are expressed slightly later, and their expression is not affected by inhibition of viral DNA replication. Late genes are expressed after viral DNA synthesis, and their expression is, in general, blocked in the presence of inhibition of viral DNA synthesis.

It can be foreseen that more data on KSHV transcription, more new transcripts, their genes and products will be determined and this compilation of KSHV transcripts will become more complete. We hope that this database will facilitate the study on KSHV gene expression and advance our understanding of KSHV replication and pathogenicity.