This virus has multiple genomic deletions (Raab-Traub et al. into the memory compartment where the computer virus persists. For egress, the infected memory cells return to the lymphoepithelium where they BIIE 0246 occasionally differentiate into plasma cells activating viral replication. The released computer virus can either infect more na?ve B cells or be amplified in the epithelium for shedding. This cycle of contamination and the quiescent state in memory B cells allow for lifetime persistence at a very low level that is remarkably stable over time. Mathematically, this is a stable fixed point where the mechanisms regulating persistence drive the state back to equilibrium when perturbed. This is the GCM of EBV persistence. Other possible sites and mechanisms of persistence will also be discussed. 1 Introduction Persistent latent contamination for the lifetime of the host is usually a defining feature of herpesviruses. Each herpesvirus has a target tissue(s) in which it persists and each has evolved a strategy for getting there and back out again. Once BIIE 0246 at the site of persistent latent contamination, the strategies coalesce in the sense that the goal is to persist latently within a very small number of cells and to minimize or eliminate viral gene expression, at least at the protein level. This in turn allows the computer virus to evade immune regulation and persist with minimal impact on the host where it will stay for the rest of its life. Acute contamination and viral reactivation to allow spread to new hosts similarly seem to have evolved for minimal impact on the host. Acute contamination should occur in childhood and is often silent. It is not a coincidence that some of the human herpesviruses are so benign and non-pathogenic that they went unnoticed until the age of AIDS where chronic immunosuppression revealed their presence. Usually, in the struggle between computer virus and host, one or the other winsif it is the host, the computer virus is usually eliminated, for example influenza. Flu goes through an acute viremic stage and then is usually cleared within a week or two (Fig. 1a). If the computer virus wins, then the host dies, for example HIV. HIV also has RGS17 an acute viremic stage but resolves into a low-level contamination. However, this is unstable and the computer virus eventually earnings to kill the host. EBV also has an acute viremic stage that resolves into a low-level contamination, but unlike HIV the computer virus then simply persists stably at this very low level (something like 1 infected cell per 5 ml of blood) for the lifetime of the host (Hadinoto et al. 2009; Khan et al. 1996; Thorley-Lawson and Allday 2008). Mathematically, this is referred to as a stable fixed point. Dynamically, it is a situation that requires the mechanisms regulating the state (persistent contamination) to drive it back to the fixed point whenever it is perturbed (Fig. 1b). Biologically, i.e., in the presence of perturbations, a stable fixed point is the only way to achieve stable long-term behaviors. BIIE 0246 Open in a separate window Fig. 1 EBV establishes a stable, benign, low-level, lifetime persistent infection. a EBV is a safe virus. EBV establishes a persistent, benign infection in virtually every human being for their entire life. This is in comparison with a virus like flu whose infection resolves in a few days or HIV which undergoes an acute infection that resolves into a long-term low-level persistent infection that eventually returns to kill the host. EBV also undergoes acute infection but then enters into a low-level persistent infection which remains stable for the life of the host. b The stable fixed point. The type of equilibrium EBV achieves is referred to mathematically as a stable fixed point. This means that the forces regulating the system act to return it to the same place after perturbation, e.g., a marble in the bottom of a bowl, whereas in an unstable fixed point, small perturbations irrevocably destroy the fixed point, e.g., a marble on top of the bowl. In real-life biology, where there are always perturbations, the only way to achieve long-term stability is through a stable fixed point EBV is a paradigm for studying the mechanism by which persistent infection is maintained in vivo. It is an unlikely candidate for this status. We lack an in vitro lytic system that would allow viral genetics to be studiedthe production of a single viral mutant is a laborious and technically challenging task (Delecluse and Hammerschmidt 2000). Certainly, no system exists for screening large numbers of viral variants and selecting mutants of choice. For a detailed discussion on the production of EBV recombinants, see the chapter authored by Henri-Jacques Delecluse. Similarly, we lack a malleable animal model to perform these studies..