The Ins and Outs of Herpesviral Capsids: Divergent Structures and Assembly Mechanisms across the Three Subfamilies

Abstract

Human herpesviruses, classified into three subfamilies, are double-stranded DNA viruses that establish lifelong latent infections within most of the world’s population and can cause severe disease, especially in immunocompromised people. There is no cure, and current preventative and therapeutic options are limited. Therefore, understanding the biology of these viruses is essential for finding new ways to stop them. Capsids play a central role in herpesvirus biology. They are sophisticated vehicles that shelter the pressurized double-stranded-DNA genomes while ensuring their delivery to defined cellular destinations on the way in and out of the host cell. Moreover, the importance of capsids for multiple key steps in the replication cycle makes their assembly an attractive therapeutic target. Recent cryo-electron microscopy reconstructions of capsids from all three subfamilies of human herpesviruses revealed not only conserved features but also remarkable structural differences. Furthermore, capsid assembly studies have suggested subfamily-specific roles of viral capsid protein homologs. In this review, we compare capsid structures, assembly mechanisms, and capsid protein functions across human herpesvirus subfamilies, highlighting the differences.

The Contribution of Kaposi’s Sarcoma-Associated Herpesvirus ORF7 and Its Zinc-Finger Motif to Viral Genome Cleavage and Capsid Formation

“…The herpesvirus terminase complex contributes to viral genome cleavage and packaging of the cleaved genomes into immature capsids. This immature capsid is thought to be assembled after the formation of procapsids or internal scaffold shell-disrupted procapsids ( 29 , 30 ). However, there are no reports describing which event (i.e., ORF7-mediated genome cleavage or ORF17-mediated internal scaffold disruption) occurs earlier during capsid formation.…”

‘Come together’—The Regulatory Interaction of Herpesviral Nuclear Egress Proteins Comprises Both Essential and Accessory Functions

“…Consequently, site-specific Ser22-phosphorylated lamins are recognized by the cellular peptidyl-prolyl cis/trans isomerase Pin1, which isomerizes the lamins towards conformational reorganization and, thus, disassembles the lamina network to provide the capsids access to the INM [ 26 , 41 , 93 ]. Concerning the membrane-specific effects of the nuclear egress pathway, several highly valuable model systems have been established, in particular representing α-herpesvirus infections [ 6 , 7 , 94 , 95 , 96 ]. While the step toward the distinct recruitment of viral capsids to the NE is still insufficiently understood, several studies investigated the budding process in which core NEC proteins are involved by inducing membrane fission.…”

“…This complex recognizes specific Pac sequences of the viral genomes and precisely cleaves the concatemers, leading to the packaging of one complete genome per capsid through the portal channel. During this packaging process, the scaffold, which is incorporated and characterizes B capsids, is disassembled by the protease, resulting in mature C capsids [ 94 ]. Until now, it is not known exactly where this packaging occurs in the nucleus, but most probably in direct or close proximity to the replication compartments as all the proteins involved in this process accumulate there.…”

The contribution of Kaposi’s sarcoma-associated herpesvirus ORF7 and its zinc-finger motif to viral genome cleavage and capsid formation

“…The herpesvirus terminase complex contributes to viral genome cleavage and packaging of the cleaved genomes into immature capsids. This immature capsid is thought to be assembled after the formation of procapsids or internal scaffold shell-disrupted procapsids (29,30).…”