The regulation of KSHV lytic reactivation by viral and cellular factors

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus that exhibits two distinct phases of infection in the host-latent and lytic. The quiescent latent phase is defined by limited expression of a subset of viral proteins and microRNAs, and an absence of virus production. KSHV periodically reactivates from latency to undergo active lytic replication, leading to production of new infectious virions. This switch from the latent to the lytic phase requires the viral protein regulator of transcription activator (RTA). RTA, along with other virally encoded proteins, is aided by host factors to facilitate this transition. Herein, we highlight the key host proteins that are involved in mediating RTA activation and KSHV lytic replication and discuss the cellular processes in which they function. We will also focus on the modulation of viral reactivation by the innate immune system, and how KSHV influences key immune signaling pathways to aid its own lifecycle.

Figure 1:. Induction of RTA and RTA-mediated regulation of lytic replication.

Transcription factors downstream of various stimuli induce RTA transcription and trigger lytic reactivation. Once transcribed, RTA mRNA is modified by m6A modifications, which is added and read by host proteins. RTA protein can also induce expression of host genes in addition to viral genes. Pro-viral genes are depicted in green, antiviral genes in red and genes that can act both pro-viral and antiviral are depicted in grey.

Figure 2:. Epigenetic modifications, DNA damage response and cellular stress pathways influence lytic reactivation.

(A) Epigenetic factors regulate the addition of histone modifications on RTA and the viral genome. Host factors shown on the left inhibit lytic reactivation by adding H3K27me3, H3K9me3 and promoting phosphorylation of histone H3. Transcriptional repressors (KAP1 and Nrf2) inhibit transcription and IFI16 promotes repressive H3K9me3 marks on the viral genome. Conversely, on the right, JMJD3 and UTX remove the transcription-suppressive H3K27me3 mark and promote lytic reactivation. Dotted lines depict the removal of histone mark. (B) Host DNA repair proteins and the DNA damage response promote lytic reactivation. Cellular ER stress sensors are pro-viral for lytic replication and reactivation while non-sense mediated decay proteins suppress lytic reactivation. Pro-viral genes are depicted in green and antiviral genes in red.

Figure 3:. Innate immune proteins and KSHV lytic reactivation.

The major DNA (cGAS, STING) and RNA (RIG-I, MDA5, MAVS, TLR7/8) sensing pathways and their components act to limit KSHV lytic reactivation. PPP6C modulates STING phosphorylation while ADAR1 and NLRX1 modulate the RIG-I/MDA5/MAVS pathway. NLR protein, NLRP1, also acts antivirally through pro-inflammatory cytokines. Caspase-8 has been demonstrated to limit the expression of IFN-β. Downstream of IFN, the ISGs, IFITs and ISG15, inhibit viral reactivation. Pro-viral genes are depicted in green and antiviral genes in red.