Regulation of KSHV Latency and Lytic Reactivation

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with three malignancies- Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). Central to the pathogenesis of these diseases is the KSHV viral life cycle, which is composed of a quiescent latent phase and a replicative lytic phase. While the establishment of latency enables persistent KSHV infection and evasion of the host immune system, lytic replication is essential for the dissemination of the virus between hosts and within the host itself. The transition between these phases, known as lytic reactivation, is controlled by a complex set of environmental, host, and viral factors. The effects of these various factors converge on the regulation of two KSHV proteins whose functions facilitate each phase of the viral life cycle-latency-associated nuclear antigen (LANA) and the master switch of KSHV reactivation, replication and transcription activator (RTA). This review presents the current understanding of how the transition between the phases of the KSHV life cycle is regulated, how the various phases contribute to KSHV pathogenesis, and how the viral life cycle can be exploited as a therapeutic target.

Keywords: Kaposi’s sarcoma-associated herpesvirus (KSHV); latency; lytic cycle; reactivation; viral life cycle.

Figure 1

The Kaposi’s sarcoma-associated herpesvirus (KSHV) genome enters a latent state after de novo infection. In some cells, early expression of lytic genes such as replication and transcription activator (RTA) triggers expression of the master organizer of latency, latency-associated nuclear antigen (LANA). LANA recruits many components of the host epigenetic machinery to promote the formation of latent KSHV episomes. A pattern of transcriptionally-permissive histone modifications across the KSHV genome gives way to a generally-repressive chromatin state, sparing robust latent gene expression. Lytic gene expression becomes minimal but poised for upregulation upon reactivation.

Figure 2

KSHV modulates host signaling pathways, chromatin structure, and gene expression to maintain latency. Viral proteins and miRNAs stimulate latency-promoting signaling pathways and chromatin modifiers. The expression and function of RTA is restricted by a variety of proteins and miRNAs from the virus and the host. LANA promotes repressive histone modifications and regulatory loops. Lytic gene expression is minimal but poised for reactivation upon shifts in the relative activities of RTA and LANA.

Figure 3

Environmental stimuli alter regulation of RTA to promote KSHV reactivation. Host signaling pathways integrate information about the cellular microenvironment that affects the expression and activity of RTA. Lytic viral proteins promote KSHV reactivation in a feed-forward loop. Various isoforms and posttranslational modifications of LANA switch it from an organizer of latency to a facilitator of the lytic cycle. The cell-intrinsic immune system is antagonized by host and viral factors to augment viral reactivation.

Figure 4

The latent and lytic stages of the KSHV life cycle drive pathogenesis. Latency maintains a population of infected cells by segregating KSHV episomes to daughter cells after mitosis. Lytic reactivation produces infectious virions that expand the pool of infected cells. Both latent and lytic factors promote tumor growth through viral oncogenes or paracrine factors. Lytic replication is sensitive to chemical inhibition, while latent episomes are difficult to target. Therapeutic interventions can force the virus out of latency, promoting cell death.