Induction of human herpesvirus-8 DNA replication and transcription by butyrate and TPA in BCBL-1 cells

Human herpesvirus-8 (HHV-8) is a gammaherpesvirus that is present primarily in a state of low level persistence in primary effusion lymphoma cell line s. Using BCBL-1 cells that harbour HHV-8 but lack Epstein-Barr virus, we de monstrate that sodium butyrate is much more effective than the phorbol este r 12-O-tetradecanoyl phorbol-13-acetate (TPA) at inducing high levels of cl ass II and III virus transcription and viral DNA replication, but also init iates apoptosis. Apoptosis occurs prior to assembly of virions when high co ncentrations of butyrate (1-3 mM) are used, whereas reduction of butyrate c oncentration to 0.3 mM decreases the rate of apoptosis and results in produ ction and secretion of enveloped virions that are visualized at high number by electron microscopy in approximately 20% of BCBL-1 cells. Butyrate indu ces much higher levels of multiple class II and class III transcripts than does TPA, including v-MIP I, v-IL-6, v-Bcl-2, vGPCR and ORF26, A decrease i n concentration of butyrate from 3 to 0.3 mM delays the peak induction of t hese genes, but peak levels remain higher than peak levels in response to T PA, These studies indicate that the massive apoptosis induced by 3 mM butyr ate could be diminished and delayed by reduction of butyrate concentration to 0.3 mM, thereby allowing expression of high levels of lytic-associated g enes and production of high yields of HHV-8 virions.