Studying Epstein–Barr Virus Pathologies and Immune Surveillance by Reconstructing EBV Infection in Mice

Epstein–Barr virus (EBV) is a g herpes virus endemic in humans and transforming human B lymphocytes. It causes a variety of human pathologies ranging from infectious mononucleosis upon acute infection to EBV-driven B-cell lymphomas. In humans, EBV-infected cells are under powerful immune surveillance by T and NK cells. If this immune surveillance is compromised as in immunosuppressed (AIDS- or posttransplantation) patients, the virus can spread from rare, EBV-containing cells and cause life-threatening pathologies. We have found that EBV immune surveillance and lymphomagenesis can be modeled in mice by targeted expression of key EBV proteins in the B-cell lineage. As EBV does not infect mouse B cells and mice have thus not coevolved with the virus, EBV exploits basic modes of the host immune response to optimize its coexistence with the host. Epstein–Barr virus (EBV)andhumans have coevolved over long time and come to a peaceful, although risky coexistence. This coexistence of virus and host relies on (i) the ability of the virus to persist as an infectious agent in the infected host for life in rare B cells invisible to the host’s immune system and (ii) a highly efficient host immune surveillance of proliferating EBV-infected, transformed B cells leading to their rapid elimination (Babcock et al. 1998; Cohen 2000; Hislop et al. 2007). The risk for the human host lies in the potent B-cell transforming activity of the virus, and thus EBV-driven lymphoproliferation and lymphomagenesis once immune surveillance is compromised. How did this intricate form of coexistence evolve? We can ask a simple question with respect to immune surveillance: Hasthehuman immunesystem evolvedto cope with an otherwise lethal viral infection, or has the virus tricked the immune system of the host into a response mode that is favorable for virus–host coexistence? EBV clearly profits from the host immune response, which protects the host from an uncontrolled outgrowth of EBV-transformed B cells, while allowing lifelong latent infection and thus efficient spreading of EBV in the human population. We address this issue by studying EBV infection in a host species which has not coevolved with the virus, but whose immune system resembles that of the human in its basic structure. Aviral strategy based on the induction of immune surveillance of virus-infected cells might well reproduce in such a scenario, whereas this would not be expected if EBV immune surveillance is based on the evolution of EBV-targeted immunological specificities in the human. Accordingly, we set out to model EBV infection in mice, a species from which EBV is absent. As EBV is unable to infect mouse B cells, we genetically targeted the expression of key EBV proteins involved in B-cell transformation and, hypothetically, the induction of immune surveillance, to the mouse B lineage.