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Abstract
Epstein-Barr virus (EBV) and related lymphocryptoviruses (LCV) from non-human primates infect B cells, transform their growth to facilitate life-long viral persistence in the host, and contribute to B cell oncogenesis. Co-evolution of LCV with their primate hosts has led to species-specificity so that LCVs preferentially immortalize B cells from their natural host in vitro. We investigated whether the master regulator of transcription, EBV nuclear antigen 2 (EBNA2), is involved in LCV species-specificity. Using recombinant EBVs, we show that EBNA2 orthologues of LCV isolated from chimpanzees, baboons, cynomolgus or rhesus macaques cannot replace EBV EBNA2 for the immortalization of human B cells. Thus, LCV species-specificity is functionally linked to viral proteins expressed during latent, growth-transforming infection. In addition, we identified three independent domains within EBNA2 that act through species-specific mechanisms. Importantly, the EBNA2 orthologues and species-specific EBNA2 domains separate unique roles for EBNA2 in the initiation of B cell immortalization from those responsible for maintaining the immortalized state. Investigating LCV species-specificity provides a novel approach to identify critical steps underlying EBV-induced B cell growth transformation, persistent infection, and oncogenesis.
Highlights
Epstein-Barr virus is a gammaherpesvirus that naturally infects most humans by adulthood, and once infected, the host harbors persistent EBV infection in a small fraction of B cells for life
By investigating LCV species-specificity, we identified two distinct steps in the process of B cell immortalization which require EBV nuclear antigen 2 (EBNA2) activity
EBNA2 signals through one domain to initiate B cell immortalization and utilizes a separate domain to maintain immortal B cell growth
Summary
Epstein-Barr virus is a gammaherpesvirus that naturally infects most humans by adulthood, and once infected, the host harbors persistent EBV infection in a small fraction of B cells for life. Viral proteins expressed during latent infection of B cells are important for persistent EBV infection, contribute to malignant B cell proliferation and lymphoma development in humans, and immortalize B cells in tissue culture. That EBV transforms B cell growth in vitro provides a valuable, tractable model system for dissecting the molecular mechanisms important for EBV’s ability to persist in humans and contribute to B cell malignancies [1]. The overall strategy of EBV proteins manipulating host cell gene expression in favor of cell growth and survival is conceptually well established. The Epstein-Barr virus nuclear antigen (EBNA) 2 interacts with various types of host cell proteins to regulate cellular and viral gene transcription. New experimental approaches will be important for advancing our understanding of how EBV transforms B cells to the level
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