Virus-Host Interactions during Epstein-Barr virus Latent Infection of B cells

Abstract

Epstein-Barr virus latently infects over 90% of the adult global population. While it generally results in a completely asymptomatic lifelong infection, EBV is associated with and the causative agent of several human malignancies, particularly in cases of immune suppression. There is extensive interplay between the virus and normal host factors and processes that are critical for maintenance of a successful latent infection. We sought to expand upon the current knowledge of this interplay in three areas: i) appropriation of the Notch signaling pathway via the host factor RBPJ, ii) global regulation of host gene expression and mRNA isoform choice, and iii) host factor regulation of the viral latent/lytic switch. Here we undertook biochemical and structural approaches to investigate the protein-protein interactions between viral latency-associated proteins and RBPJ. This revealed new information differentiating the surfaces of RBPJ bound by viral and Notch signaling proteins. Furthermore we utilized a novel algorithm with microarray data prior to infection and after establishment of latency in B cells to study host mRNA changes associated with latent infection. Here we identified transcription and splicing factors to be uniquely regulated by EBV at the level of mRNA isoform. Finally we identified two host factors that regulate the switch between latent and lytic replication based on their EBV-directed isoform usage.