Interferon, the Cell Cycle and Herpesvirus

Herpesviruses are a large group of successful, and widely distributed, double-stranded DNA viruses of serious medical and veterinary importance. Although they infect many different animal species, they are host specific at the individual species level. On the other hand, they share a common life style, first with an acute infection in epithelial cells which is followed by the establishment of persistence in neurons (┙-herpesvirus), monocytes (┚herpesvirus), or B lymphocytes (┛-herpesvirus). The varied pathology of these different groups of herpesvirus is typically associated with reactivation of a persistent infection and the subsequent production of virus. Thus, the immune system faces three distinct challenges: how to control the acute phase, the persistent virus, and the consequences of reactivation. For this reason, control of herpesvirus infection calls on the many functional arms of both the innate and adaptive immune systems, which in turn have exerted the selection pressure that has driven the evolution of many strategies of immune evasion. This chapter will focus on herpesviruses host evasion genes manipulating cell cycle progression and interferon. All members of order Herpesvirales have a biphasic infection cycle consisting of replicative (lytic) and latent phases. During the lytic cycle and viral reactivation, most of the viral genes are expressed in a cascade manner and large numbers of infectious virus particles are released. Latency, on the other hand, is characterized by limited gene expression, lack of virion production and, in the case of ┛-herpesviruses, is associated with immortalization and transformation of infected cells. Virus survival at each phase depends on evasion of the host immune response. Thus, the escape from immune detection in the early phases of infection may be almost as important as in the latent phase (Vider-Shalit et al., 2007). The typical herpesvirus life cycle is a challenge for the development of a global antiviral therapy or protective vaccines. Although all herpesviruses present a similar lytic phase and are able to establish latency in a specific set of cells, the cell types in which they remain latent, and thus have evolved virus host cell evasion molecular mechanisms, differ widely from one virus to another (Pellet & Roizman, 2007). One promising approach is to explore new viral targets, particularly viral proteins involved in host immune evasion. An effective herpesvirus vaccine would therefore be a genetically targeted mutant with one or more nonimmunogenic host evasion genes deleted, and with appropriate investigation of the pathogenesis to ensure safety. Bioinformatic analysis of putative homologues showed that 39 conserved herpesvirus protein families and 20 single proteins had significant sequence similarity to human gene products,