Nuclear Innate Immune DNA Sensor IFI16 Is Degraded during Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus (KSHV): Role of IFI16 in Maintenance of KSHV Latency

Abstract

IMPORTANCELike all herpesviruses, latency is an integral part of the life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV), an etiological agent for many human cancers. Herpesviruses utilize viral and host factors to successfully evade the host immune system to maintain latency. Reactivation is a complex event where the latent episomal viral genome springs back to active transcription of lytic cycle genes. Our studies reveal that KSHV has evolved to utilize the innate immune sensor IFI16 to keep lytic cycle transcription in dormancy. We demonstrate that IFI16 binds to the lytic gene promoter, acts as a transcriptional repressor, and thereby helps to maintain latency. We also discovered that during the late stage of lytic replication, KSHV selectively degrades IFI16, thus relieving transcriptional repression. This is the first report to demonstrate the role of IFI16 in latency maintenance of a herpesvirus, and further understanding will lead to the development of strategies to eliminate latent infection. The human gammaherpesvirus Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), also referred to as human herpesvirus 8 (HHV-8), is an oncogenic virus etiologically associated with KS, primary effusion B-cell lymphoma (PEL) or body cavity B-cell lymphoma (BCBL), and plasmablastic multicentric Castleman's disease (pMCD) (1-3). In vivo, KSHV DNA and transcripts have been identified in human B cells, endothelial cells, epithelial cells, macrophages, and keratinocytes (3, 4). Similar to other herpesviruses, KSHV undergoes two distinguishable phases in its life cycle: latent and lytic infection (3, 4). During primary infection, KSHV initially establishes latent infection in specific target cells, during which multiple copies of the viral genome are stably maintained as extrachromosomal episomes (3,5). Only a few viral genes, primarily localized in the major latency locus of the genome, are expressed during this phase. These gene products bestow numerous essential functionalities to the dormant viral genome, such as evading host immune surveillance (6), promoting cellular proliferation (7-9), maintaining the viral episome (10), and tightly suppressing viral lytic gene expression (11). However, both spontaneous reactivation and induced reactivation of the latent genome occur, resulting in the systematic expression of the full repertoire of viral genes, which leads to viral genome replication and virion production (4). Previous studies suggested that lytic reactivation

Host cell restriction factors that limit transcription and replication of human papillomavirus

“…IFI16 is a restriction factor for several other DNA viruses, including HSV-1 and HCMV (Gariano et al, 2012; Orzalli et al, 2013), and it induces anti-viral inflammasome activity against KSHV and EBV (Ansari et al, 2013; Roy et al, 2016). However, while IFI16 restricts incoming HSV-1 DNA, it does not restrict SV40 DNA packaged in nucleosomes and delivered to the nucleus by transfection (Orzalli et al, 2013).…”

The Role of Nuclear Antiviral Factors against Invading DNA Viruses: The Immediate Fate of Incoming Viral Genomes

“…These data highlight again that, although PML-NBs and/or its components could be involved in the establishment and/or maintenance of herpesviral latency, it is unlikely that a common mechanism of interplay between PML-NBs and viral genomes during latency exists for all viruses. Intriguingly, a recent study on KSHV has suggested a role for IFI16 in maintenance of latent infection [105]. In summary, the potential role of known and yet to be discovered nuclear antiviral factors in latent infection is of major interest, and further studies are needed to understand how latency is established on incoming genomes.…”

Viral Inhibition of PRR-Mediated Innate Immune Response: Learning from KSHV Evasion Strategies

“…Furthermore, IFI16 has been shown to be involved in the induction of IFN-β production during KSHV de novo infection by targeting the IFI16-STING-IRF3 axis (Ansari et al, 2015). Very recently, Roy et al (2016) demonstrated that IFI16 binds to the lytic gene promoter and acts as a transcriptional repressor to maintain viral latency. Overall, these observations indicate that the efficient maintenance of latency by IFI16 and the activation of the IFI16 inflammasome by latent KSHV could drive KSHV-associated inflammatory cytokine syndromes, like MCD.…”