Maturation and egress

Excerpt

The assembly of betaherpesviruses, specifically cytomegaloviruses, is a topic of considerable interest to virologists and structural biologists. These viruses are among the largest and most complex animal viruses and encode a large number of proteins. Some clinical isolates of human cytomegalovirus (HCMV) have been predicted to contain as many as 250 ORFs (Chee et al., ; Murphy et al., 2003), while other authors have suggested that the coding capacity of HCMV may actually be on the order of 165 ORFs (see Chapter 14). Although the number of virus-encoded proteins that are incorporated into the infectious particle is unknown, estimates from several laboratories suggest that it could approach 100 proteins (Varnum et al., 2004). In addition, the particle also contains an unknown number of host cell proteins, some that may have functional significance in the replicative cycle of these viruses (Varnum et al., 2004). Thus, the complexity of virus assembly rivals that of some cellular organelles. Furthermore, CMVs do not arrest host cell protein synthesis even at late phases of replication as do the alphaherpesviruses and therefore during their assembly can either compete with host cell protein synthetic and targeting pathways or more likely, express viral specific functions that modulate host cellular pathways to optimize viral protein synthesis and transport. Identification of these virus-specified host cell modifications together with their interactions with virion proteins will aid in the understanding of the assembly of this virus. Similar approaches have provided a reasonably detailed view of the assembly pathways of bacteriophages and eukaryotic RNA viruses, including HIV-1, and these studies have in some instances served as templates for investigations of DNA virus assembly. However, herpesviruses encode vastly more virion proteins compared to RNA viruses, and assembly takes place in both nuclear and cytoplasmic compartments. Definitive studies of capsid assembly have been carried out in alphaherpesviruses and have been extended to include in vitro, cell free assembly of the herpes simplex viral (HSV) capsid (Newcomb et al., 1994). Many of the capsid proteins of CMVs and other betaherpesviruses share extensive structural and functional homology with HSV capsid proteins and cryoelectron microscopic analysis of the HCMV capsid suggests similar, but not identical, capsid structure (Butcher et al., ; Chen et al., ; Trus et al., ; Zhou et al., 1999, 2000). The most structurally diverse region of the herpesvirus virion appears to be the tegument which is composed of a great many betaherpesvirus- and CMV-unique proteins. Although proteins with homologous functions localized to this region of the virus can be readily identified for many different herpesviruses, only a limited number of these proteins exhibit significant structural homologies (Mocarski and Tan Courcelle, C., 2001). Despite these similarities, a large number of structural proteins appear to be unique for each subfamily of herpesviruses and in some cases, such as HCMV, several tegument proteins have no counterparts in alphaherpesviruses (Mocarski and Tan Courcelle, C., 2001). Together, these findings suggest that, although common themes likely exist for herpesvirus assembly, it is almost certain that distinct aspects of the assembly pathway of each of these viruses will be identified and these differences in the assembly of different herpes viruses could point to key features of the infectious cycle of these viruses.