The cell cycle, cyclin-dependent kinases, and viral infections: new horizons and unexpected connections

The genomes of small DNA viruses such as papilloma and polyomaviruses code for few or no DNA replication proteins. Consequently, these viruses depend on cellular DNA replication proteins to replicate their genomes and replicate only when the infected cell progresses into S-phase, when these proteins are active. As a consequence of this strict dependence, the relationship between replication of the small DNA viruses and the cell cycle was obvious from the very early studies. The genomes of larger DNA viruses such as adeno- and herpes-viruses, in contrast, encode many of the proteins required for DNA replication. Some of the larger DNA viruses such as adenoviruses, however, also replicate only in S-phase because expression of viral DNA replication proteins is regulated by cellular factors that are activated in S-phase. Other large DNA viruses such as herpes simplex viruses (HSV) can replicate in arrested cells such as neurons, without inducing progression into S-phase. The relationships between cell cycle and replication of these last viruses are, thus, so subtle that their replication was long thought to be independent from cellular proteins whose activities are regulated in a cell cycle dependent manner. In contrast to this hypothesis, recent studies have shown that replication of HSV and other large DNA viruses requires cellular proteins whose activities are normally regulated in a cell cycle dependent manner, such as the cyclin-dependent kinases (cdks). Many excellent reviews on the interactions between cellular proteins involved in cell cycle regulation and smaller DNA viruses (parvo, papilloma, polyoma and adenoviruses) have been published (for example, see (1, 2)). Many reviews on cell cycle regulation also discuss the interactions between the cell cycle and the smaller DNA viruses (for example, see (3-5)). Herein, we will review these relationships only briefly, while focusing on the interactions between cell cycle proteins such as cdks and herpes-, retro, and hepadna-viruses. We will then succinctly discuss the surprising relationships between cdks and replication of some cytoplasmic RNA viruses. Lastly, we will present the possibility of applying the new information on the dependence of viral replication on cyclin-dependent kinases to the development of novel antiviral drugs.