Herpesvirus lytic replication and the cell cycle: arresting new developments.

It has been clear for a number of years that small DNA tumor viruses such as simian virus 40 (SV40) and papillomavirus interact with cell cycle control pathways during lytic replication in a way that promotes entry into the S phase of the cell cycle. Since these viruses do not code for their own DNA polymerase or other accessory factors that support DNA replication, this strategy is a means of subverting the cell cycle control machinery to support viral DNA replication. In contrast to these viruses, herpesviruses contain a much greater genetic complexity that encodes a viral DNA polymerase, as well as accessory factors involved in generating nucleotide pools, etc. Indeed, herpesviruses have evolved a distinct viral replication strategy and, unlike SV40 and papillomavirus, herpesviruses do not require an S-phase environment to support viral replication. Further, numerous studies from several different herpesvirus systems have provided unifying evidence that these viruses encode factors that elicit a cell cycle block, thereby actively preventing entry into S phase. The conserved nature of this function across different members of the herpesvirus family suggests that it is an integral aspect of the herpesvirus replication strategy. As discussed here, regulation of the cell cycle during herpesvirus DNA replication has evolved as a complex series of interactions involving multiple viral factors, further implying an important role for this function in the life cycle of the virus. The interaction between herpesviruses and the cell cycle regulatory machinery is even more interesting, however. While viral factors elicit cell cycle arrest signaling, some viral factors also activate certain cell cycle regulatory pathways that would normally promote cell cycle progression. These cell cycle-promoting functions also appear to be important since inhibition of these pathways inhibits viral replication. Therefore, it appears that although herpesviruses elicit cell cycle arrest, their complex interactions with the cell cycle regulatory machinery likely evolved to poise the cell in a precise cell cycle position which most favors viral replication. Although a scattering of publications prior to 1995 provided hints into the interaction between herpesviruses and cell cycle control pathways, accumulating interest from several different laboratories over the past 5 or 6 years has begun to provide general underlying themes into this issue as well as elucidate some of the details of these interactions. These recent studies have been carried out in a largely independent fashion with alpha-, beta-, and gammaherpesvirus systems (primarily herpes simplex virus [HSV], cytomegalovirus [CMV], and EpsteinBarr virus [EBV]). The purpose of this review is to bridge the current understanding of virus-cell cycle interactions for these three herpesvirus lytic replication systems. To this end, I have provided a fairly detailed summary of the existing experimental data for each of these herpesvirus systems, which will hopefully serve as a tool to apprise investigators of related progress outside of their respective disciplines. At the end of this review, I have commented on some of the common strategies utilized by these viruses to achieve efficient cell synchronization during lytic replication.