Figure 1: Schematic illustration of mechanisms of KSHV latency and reactivation. During primary infection, KSHV activates innate immune responses such as IFN-α/β and IRFs and multiple cell survival pathways including NF-κB, c-Myc, and PI3K/AKT, all of which repress KSHV lytic replication. Expression of KSHV latent products including LANA, vCyclin, vFLIP, and a cluster of miRNAs also inhibits KSHV lytic replication. As a result, KSHV establishes latency following primary infection. During latency, most parts of viral genome are epigenetically silenced and contain both active and repressive histone marks (black triangle) with the exception of the latent locus, which is transcribed and contains only active histone marks (black cycle). KSHV latent products enhance/maintain latency by promoting cell survival and facilitating the viral episome replication and segregation. Several physiological factors including hypoxia, HIV infection, inflammatory cytokines, oxidative stress, and ROS can induce RTA expression by activating specific cellular pathways and transcriptional factors including MEK/ERK, JNK, p38, AP-1, Ets-1, HIF1/2, PKC, and Notch. RTA interacts with several host proteins such as XBP-1, Notch, and C/EBPα, as well as viral proteins such as MTA and kb-ZIP, to quickly remove the repression histone marks on KSHV genome, resulting in the expression of viral lytic genes and activation of the entire viral lytic transcriptional program.