Recent advances in understanding Kaposi's sarcoma-associated herpesvirus

Abstract

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is an oncogenic human herpesvirus. KSHV is associated with three cancers in the human population: KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KS is the leading cause of cancer in HIV-infected individuals. In this review, we discuss the most recent discoveries behind the mechanisms of KSHV latency maintenance and lytic replication. We also review current therapies for KSHV-associated cancers.

Keywords: KSHV; Kaposi’s sarcoma-associated herpesvirus; multicentric Castleman’s disease; primary effusion lymphoma.

Figure 1.. Schematic of Kaposi’s sarcoma-associated herpesvirus (KSHV) latent/lytic switch.

During latency, only a few viral proteins and microRNAs are expressed. The KSHV latent protein latency-associated nuclear antigen (LANA) establishes latency and tethers the KSHV episome to host chromosomes. During this phase of the KSHV lifecycle, lytic genes are suppressed. This suppression occurs due to chromatin modifications that put the replication and transcription activator (RTA) gene and other lytic genes in a closed chromatin conformation with histones that contain inhibitory marks (histones shown in red). These inhibitory modifications are likely regulated by histone deacetylases (HDACs) and tousled-like kinases (TLKs). LANA (lime green semi-circle) also suppresses RTA expression through a complex with poly-SUMO-2-ylated KAP1 (pink tear-drop with yellow circle) and nuclear factor E2-related factor 2 (Nrf2) (tan L) that binds to the RTA gene promoter, further inhibiting transcription (indicated by the red arrow). Upon addition of inducers of the latent/lytic switch, e.g. cellular stress or 12-O-tetradecanoylphorbol-13-acetate (TPA), the chromatin around lytic genes is opened. The histones associated with lytic genes lack inhibitory marks and contain activation marks (histones shown in green). This results in gene transcription from the RTA promoter being activated (green arrow), allowing for RTA expression and transactivation of downstream lytic genes.