Epstein-Barr virus and B-cell co-opted functions of the endogenous retrovirus envelope protein, Syncytin-1

项目总结

Project Summary Aberrant expression of human endogenous retroviruses (HERVs) has been associated with enhanced pathology in a number of cancers and autoimmune diseases (1, 2). One of these HERV elements is the protein Syncytin- 1, encoded by the ERVW1 gene, and is essential for placental development. Although these elements are epigenetically silenced after embryonic development, exogenous viral infections, such as Epstein-Barr virus (EBV), have been linked to enhanced expression of HERVs (3-7). EBV, a gamma-herpesvirus, is the cause of infectious mononucleosis and associated with a number of cancers including Burkitt lymphoma (BL), nasopharyngeal cell carcinoma, Hodgkin’s disease, and other lymphoproliferative diseases. With no vaccine or antiviral drug available, EBV is an important pathogen to study. Primary infection with EBV begins with its attachment, fusion, and entry into oropharyngeal epithelial cells. EBV then spreads to memory B cells where it persists for the life of the host, generally in a latent state. During latency, only a small subset of EBV genes are expressed (8). Periodically, EBV undergoes lytic activation in a subset of B cells to persist in the population. Importantly, lytic activation of EBV not only increases risks for development of EBV-related cancers, particularly in immunocompromised hosts, but may also be exploited to treat EBV-associated cancers in an approach known as oncolytic therapy. Lytic activation is characterized by the expression of over 80% of EBV genes, many of which serve in immune evasion, regulation of apoptosis, and blockade of host protein synthesis. This latter phenomenon results in the downregulation of most host genes, known as global host shutoff, and the preferential expression of viral genes (9). Despite global host shutoff, I find that the HERV element ERVW1, which encodes Syncytin-1, increases in both transcript and protein levels during lytic activation of EBV in infected B cells. This, coupled with the fact that similar epigenetic mechanisms silence both HERVs and latent EBV, leads me to predict that EBV may spare and/or activate Syncytin-1 for a specific purpose during lytic replication. This study will elucidate the functions of Syncytin-1 during EBV infection of B cells. It will reveal why Syncytin-1 The study will further characterize the consequences of Syncytin-1 depletion and mutagenesis on B cell biology as well as the interactions of Syncytin-1 broadly with B cell proteins and specifically with the PI3K/Akt/mTOR signaling pathway, known to trigger EBV lytic replication, B cell survival, and proliferation. The proposed studies are aimed at revealing mechanisms governing the role of Syncytin-1 in lymphoproliferative diseases and B cell lymphomas. is upregulated despite host cell shutoff by delineating Syncytin-1’s influence during the EBV lytic cycle. Hypothesis: I hypothesize that Syncytin-1 is selectively spared by EBV because it has a role in potentiating lytic replication. I also hypothesize that Syncytin-1 plays a role in B cell biology by promoting cell proliferation. Aim 1: Define the contribution of Syncytin-1 to Epstein-Barr virus lytic cycle. Aim 2: Determine the functional role of Syncytin-1 in B cell proliferation.