Conspiring with the enemy: IRF-3 supports latent gammaherpesvirus infection of germinal center B cells

Abstract

Abstract Gammaherpesviruses (GHVs) are ubiquitous pathogens that establish lifelong infections in their host. Importantly, these viruses manipulate B cell differentiation to establish long-term latency and are associated with a variety of B cell lymphomas. In a clever feat, GHVs infect naïve B cells and drive the infected B cells along with uninfected bystanders into the germinal center response, where the rapid expansion of B cells results in an exponential increase in the latent viral reservoir. Germinal center B cells are also thought to be the target of malignant transformation. Type I Interferon (IFN), a major antiviral system of the host, is transcriptionally activated by several host factors, including Interferon regulatory factor 3 (IRF-3). IRF-3 restricts GHV lytic replication during acute infection. Importantly, nothing is known about the role of IRF-3 during chronic GHV infection that is almost exclusively represented by the latent viral life cycle. Additionally, no studies have examined the effect of IRF-3 on the GHV-driven germinal center response. Unexpectedly and in contrast to the phenotype during acute infection, we discovered that IRF-3 deficiency attenuated the establishment of chronic GHV infection, revealing a a pro-viral role of IRF-3 during viral latency. Further, while there was no effect on germinal center B cell expansion in the absence of IRF-3, the efficiency of germinal center B cell infection by GHV was reduced. Current studies are examining how IRF-3 may be facilitating latent infection of germinal center B cells. This is, to our knowledge, is the first example of IRF-3 functioning in a pro-viral manner in the context of chronic virus infection.