
<ArticleTitle>Transcription pattern of human herpesvirus 8 <prot>open reading frame K3</prot> in primary effusion lymphoma and Kaposi's sarcoma.</ArticleTitle>
<AbstractText>Human herpesvirus 8 (HHV-8) is found in immunoblastic B cells of patients with multicentric Castleman's disease (MCD) and, predominantly in a latent form, in primary effusion lymphoma (PEL) cells and Kaposi's sarcoma (KS) spindle cells. Recent studies have shown that upon reactivation, HHV-8 expresses factors that downregulate major histocompatibility class I proteins and coactivation molecules and that may enable productively infected cells to escape cytotoxic T lymphocytes and natural killer cell responses. One of these viral factors is encoded by <prot>open reading frame (ORF) K3</prot>. Here we show that in PEL cells, <prot>ORF K3</prot> is expressed through viral transcripts that are induced very early upon virus reactivation, including bicistronic RNA molecules containing coding sequences from viral <prot>ORFs K3</prot> and 70. Specifically, we found that a bicistronic transcript was expressed in the absence of de novo protein synthesis, thereby identifying a novel HHV-8 immediate-early gene product. Several features of the RNA molecules encoding the <prot>K3</prot> product, including multiple transcriptional start sites, multiple donor splicing sites, and potential alternative ATG usage, suggest that there exists a finely tuned modulation of <prot>ORF K3</prot> expression. By contrast, <prot>ORF K3</prot> transcripts are not detected in the majority of cells present in KS lesions that are latently infected by the virus, suggesting that there are other, as-yet-unknown mechanisms of immune evasion for infected KS spindle cells. Nevertheless, because HHV-8 viremia precedes the development of KS lesions and is associated with the recrudescence of MCD symptoms, the prompt expression of <prot>ORF K3</prot> in productively infected circulating cells may be important for virus pathogenesis. Thus, molecules targeting host or viral factors that activate <prot>ORF K3</prot> expression or inactivate the biological functions of the <prot>K3</prot> product should be exploited for the prevention or treatment of HHV-8-associated diseases in at-risk individuals.</AbstractText>
