Nuclear sensing of viral DNA, epigenetic regulation of herpes simplex virus infection, and innate immunity

Abstract

Herpes simplex virus (HSV) undergoes a lytic infection in epithelial cells and a latent infection in neuronal cells, and epigenetic mechanisms play a major role in the differential gene expression under the two conditions. HSV viron DNA is not associated with histones but is rapidly loaded with heterochromatin upon entry into the cell. Viral proteins promote reversal of the epigenetic silencing in epithelial cells while the viral latency-associated transcript promotes additional heterochromatin in neuronal cells. The cellular sensors that initiate the chromatinization of foreign DNA have not been fully defined. IFI16 and cGAS are both essential for innate sensing of HSV DNA, and new evidence shows how they work together to initiate innate signaling. IFI16 also plays a role in the heterochromatinization of HSV DNA, and this review will examine how IFI16 integrates epigenetic regulation and innate sensing of foreign viral DNA to show how these two responses are related.

Keywords: DNA virus; Epigenetics; IFI16; Innate immunity; cGAS.

Figure 1. Model for epigenetic regulation of the lytic versus latent infection decision by HSV

(A). Following infection of epithelial cells, the capsid is transported to the nuclear pore where the viral DNA is released into the nucleus where it rapidly circularizes and becomes associated with histones bearing heterochromatin marks. VP16 from the virion tegument forms a complex with HCF-1 and Oct1 that binds to viral IE promoters and HCF-1 recruits histone modification enzymes and chromatin remodeling complexes that decrease histone association with viral IE genes and increase euchromatin marks on the remaining associated histones. ICP0 is expressed as an IE protein and it promotes similar processes on the rest of the genome. (B). Following infection of neuronal cells, the capsid is also transported to the nuclear pore where the viral DNA is released into the nucleus where it rapidly circularizes and becomes associated with histones. VP16 cannot be transported into the neuronal nucleus, and HCF-1 is not localized in the nucleus so viral IE genes are not transcribed efficiently. Instead, the latency-associated transcript is expressed and it promotes the association of facultative heterochromatin marks on the viral chromatin (Copyright, Lynne Chang, Priya Raja, and David Knipe).

Figure 2. Model of nuclear HSV-1 DNA sensing, innate signaling, and epigenetic regulation by IFI16 and inhibition by ICP0

HSV capsids in the cytoplasm traffic to nuclear pores where viral DNA is released into the nucleus. The viral DNA rapidly circularizes, and nuclear IFI16 binds to the viral DNA and multimerizes, initiating a nuclear-to-cytoplasmic signaling cascade that activates IRF-3, which dimerizes and translocates to the nucleus. Immediate-early expression of ICP0 promotes degradation of IFI16 to inhibit subsequent IRF-3 signaling and IFN-α expression. The multimerized IFI16 on the viral DNA also recruits histone modification complexes that add H3K9me3 modifications to the viral chromatin, resulting in epigenetic silencing of the viral genes. (Copyright, Megan Orzalli and David Knipe).