Structures and Divergent Mechanisms in Capsid Maturation and Stabilization Following Genome Packaging of Human Cytomegalovirus and Herpesviruses

Abstract

Herpesviruses are the causative agents of several diseases. Infections are generally mild or asymptomatic in immunocompetent individuals. In contrast, herpesvirus infections continue to contribute to significant morbidity and mortality in immunocompromised patients. Few drugs are available for the treatment of human herpesvirus infections, mainly targeting the viral DNA polymerase. Moreover, no successful therapeutic options are available for the Epstein–Barr virus or human herpesvirus 8. Most licensed drugs share the same mechanism of action of targeting the viral polymerase and thus blocking DNA polymerization. Resistances to antiviral drugs have been observed for human cytomegalovirus, herpes simplex virus and varicella-zoster virus. A new terminase inhibitor, letermovir, recently proved effective against human cytomegalovirus. However, the letermovir has no significant activity against other herpesviruses. New antivirals targeting other replication steps, such as capsid maturation or DNA packaging, and inducing fewer adverse effects are therefore needed. Targeting capsid assembly or DNA packaging provides additional options for the development of new drugs. In this review, we summarize recent findings on capsid assembly and DNA packaging. We also described what is known about the structure and function of capsid and terminase proteins to identify novels targets for the development of new therapeutic options.

UL34 Deletion Restricts Human Cytomegalovirus Capsid Formation and Maturation

“…Given that these transcripts were present at similar levels in WT and ΔUL34 infections ( Figure S3C ), the capsid maturation defects observed are not due to the down-regulation of essential capsid maturation gene expression ( Figure 5 A–M). As the precise molecular details describing capsid assembly and maturation are emerging [ 79 ], with the phenotype observed in ΔUL34 infection, UL34 may be involved in these processes.…”

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

“…Capsids assemble in the nucleus from the MCP, triplexes, SCP, protease, scaffold, and portal proteins (Figure 2) (reviewed in [6,17]). (Additional, so-called auxiliary, proteins are also found on the capsids, but they are less conserved across subfamilies and are discussed in more detail in Section 3).…”

“…Capsid assembly is thought to be nucleated by the portal complex and mediated by the MCP and triplexes that form a spherical procapsid around the scaffold and the protease (Figure 2) [25][26][27]. Concomitantly, concatemeric DNA is cleaved into unit-length genomes and brought to the capsid for packaging by the terminase complex, a group of three viral proteins (UL15, UL28, and UL33 in HSV-1 [28]) essential for DNA packaging [6,17]. Binding of the terminase complex to the portal triggers the protease to cleave the scaffold, which causes angularization of the procapsid [24,[29][30][31][32].…”

UL49 is an essential subunit of the viral pre-initiation complex that regulates human cytomegalovirus gene transcription

“…Nuclear stages predominantly take place in the replication compartment (RC), which is a virally induced inclusion ( Caragliano et al., 2022 ). Here the viral genome is replicated by a rolling circle mechanism to produce concatemers, viral gene transcription takes place, capsids assemble, and genomes are cleaved and packaged ( Muller et al., 2021 ). Maturing capsids exit the nucleus ( Sanchez and Britt, 2021 ) and traffic into the cytoplasmic viral assembly compartment (vAC) for final regimentation, envelopment, and egress ( Alwine, 2012 ).…”