DNA viruses encode a diverse repertoire of effective strategies for immune evasion. Varicella zoster virus (VZV) is a clinically important double-stranded DNA herpesvirus that causes chickenpox and shingles, and poses significant medical burden worldwide. VZV infection is difficult to recapitulate in the laboratory setting due to its cell-associated nature in culture, which has made it largely recalcitrant to biomolecular characterisation. There is poor understanding of its ability to modulate immunity-associated intracellular signalling pathways, including those leading to programmed cell death. During viral incursion, programmed cell death is activated in response to internal or external stressors, in order to contain local foci of infection within tissues.
We have recently described a novel mechanism by which VZV abrogates caspase-dependent apoptosis [1]. Using a combination of virological, biochemical and biophysical analyses, we have demonstrated that ZBP1, an intracellular nucleic acid sensor, detects VZV during infection, and forms a signalling platform that is capable of initiating cell death by apoptosis. Our results show, however, that VZV subverts this process through the activity of its ORF20 protein, which serves as an inhibitor of apoptosis. ZBP1 contains a RHIM (RIP Homotypic Interaction Motif) sequence that mediates protein:protein interactions required for immunity-associated signalling [2]. We have identified a RHIM within ORF20, which allows it to interact with ZBP1 to form large, ultrastable, heteromeric amyloid structures. We propose the formation of these viral:human protein assemblies sequesters ZBP1 into a structure that is incapable of signalling for apoptosis, thereby preventing viral clearance. These findings illuminate fundamental aspects of infection by an important, ubiquitous virus and broaden our understanding of the complex mechanisms employed by viruses to establish pathology.