Molecular Biology of KSHV Lytic Reactivation

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) primarily persists as a latent episome in infected cells. During latent infection, only a limited number of viral genes are expressed that help to maintain the viral episome and prevent lytic reactivation. The latent KSHV genome persists as a highly ordered chromatin structure with bivalent chromatin marks at the promoter-regulatory region of the major immediate-early gene promoter. Various stimuli can induce chromatin modifications to an active euchromatic epigenetic mark, leading to the expression of genes required for the transition from the latent to the lytic phase of KSHV life cycle. Enhanced replication and transcription activator (RTA) gene expression triggers a cascade of events, resulting in the modulation of various cellular pathways to support viral DNA synthesis. RTA also binds to the origin of lytic DNA replication to recruit viral, as well as cellular, proteins for the initiation of the lytic DNA replication of KSHV. In this review we will discuss some of the pivotal genetic and epigenetic factors that control KSHV reactivation from the transcriptionally restricted latent program.

Kaposi's sarcoma-associated herpesvirus-encoded LANA associates with glucocorticoid receptor and enhances its transcriptional activities

“…LANA is a 222-232-kDa nuclear protein expressed from open reading frame 73 of the KSHV genome [4,7,8,9]. LANA contains several conserved sequences including acidic-, proline-, and glutamine-rich domains as well as a zinc finger DNA-binding domain, leucine zipper, and potential nuclear localization signal.…”

“…Only limited regions are activated in KSHV during latent infection. In contrast, the full repertoire of viral genes is activated in a temporally regulated manner during the lytic phase [1,4]. Two major KSHV products, LANA and RTA (replication and transcription activator), are believed to interact with each other, leading to switching between latent and lytic phases [36].…”

“…RTA acts as an initiator and regulator of KSHV lytic DNA replication, and LANA represses RTA gene expression. Importantly, this inhibitory effect of LANA is partly regulated by its post-translational modification including arginine methylation, phosphorylation, and sumoylation [4,37,38]. KSHV reactivation is also induced by certain stimuli such as viral co-infection as well as hypo-and hyper-oxidative responses [1,4].…”

“…Importantly, this inhibitory effect of LANA is partly regulated by its post-translational modification including arginine methylation, phosphorylation, and sumoylation [4,37,38]. KSHV reactivation is also induced by certain stimuli such as viral co-infection as well as hypo-and hyper-oxidative responses [1,4]. Several reports indicate the involvement of GCs in KSHV reactivation [20][21][22][23][24][25][26][27].…”

“…Numerous proteins encoded by the KSHV open reading frame during latency and lytic cycles of the virus have been identified, of which some are believed to transform the infected cells [1,4]. Although KSHV was originally isolated from Kaposi's sarcoma (KS), the virus is also related to primary effusion lymphoma and multicentric Castleman disease [5,6].…”