This proposal represents a close collaborative effort between the Jardetzky and Longnecker laboratories focusing on understanding Epstein-Barr virus (EBV) entry into target cells and on developing novel approaches to therapeutic intervention. The entry of EBV into both epithelial cells and B cells is directly relevant to the Program Announcement for AIDS-related malignancies. Both cell types are EBV target tissues in human hosts and the presence of EBV has been linked to cancerous growth in both tissues, in particular after the development of HIV/AIDS. Virus entry inhibitors have been identified for a number of viruses, including HIV, and we have demonstrated that EBV infection can also be blocked with high affinity peptide inhibitors. We hypothesize that inhibition of EBV entry may provide a therapeutic alternative in preventing or controlling the development of EBV-associated malignancies and/or pathologies in HIV/AIDS patients. We have developed a novel, mechanism-guided approach to designing EBV entry/membrane fusion inhibitors, based on understanding gH/gL glycoprotein structure and function, and demonstrated that gH/gL is a viable target for high affinity entry inhibitors. The current proposal continues this integrated research program on the EBV entry mechanism, addressing key hypotheses regarding the function and inhibition of the EBV gH/gL protein.

Public Health Relevance

This proposed research represents a collaborative research program between Dr. Longnecker and Dr. Jardetzky to define the molecular mechanisms involved in Epstein-Barr virus (EBV) entry into B lymphocytes, the major target cell of EBV in human hosts, and to develop novel inhibitor approaches to blocking viral infection. EBV is associated with a variety of hematopoietic, epithelial, and lymphoproliferative diseases, evident in AIDS patients. The proposed research may result in the identification of new therapeutics for EBV infections as well as the herpesvirus family in general, of which EBV is a member.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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AIDS Discovery and Development of Therapeutics Study Section (ADDT)
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Daschner, Phillip J
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Stanford University
Schools of Medicine
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Sathiyamoorthy, Karthik; Hu, Yao Xiong; Möhl, Britta S et al. (2016) Structural basis for Epstein-Barr virus host cell tropism mediated by gp42 and gHgL entry glycoproteins. Nat Commun 7:13557
Möhl, Britta S; Schröter, Christina; Klupp, Barbara G et al. (2016) Comparative Mutagenesis of Pseudorabies Virus and Epstein-Barr Virus gH Identifies a Structural Determinant within Domain III of gH Required for Surface Expression and Entry Function. J Virol 90:2285-93
Chen, Jia; Jardetzky, Theodore S; Longnecker, Richard (2016) The Cytoplasmic Tail Domain of Epstein-Barr Virus gH Regulates Membrane Fusion Activity through Altering gH Binding to gp42 and Epithelial Cell Attachment. MBio 7:
Möhl, Britta S; Chen, Jia; Sathiyamoorthy, Karthik et al. (2016) Structural and Mechanistic Insights into the Tropism of Epstein-Barr Virus. Mol Cells 39:286-91
Rowe, Cynthia L; Chen, Jia; Jardetzky, Theodore S et al. (2015) Membrane anchoring of Epstein-Barr virus gp42 inhibits fusion with B cells even with increased flexibility allowed by engineered spacers. MBio 6:
Chen, Jia; Zhang, Xianming; Jardetzky, Theodore S et al. (2014) The Epstein-Barr virus (EBV) glycoprotein B cytoplasmic C-terminal tail domain regulates the energy requirement for EBV-induced membrane fusion. J Virol 88:11686-95
Sathiyamoorthy, Karthik; Jiang, Jiansen; Hu, Yao Xiong et al. (2014) Assembly and architecture of the EBV B cell entry triggering complex. PLoS Pathog 10:e1004309
Fan, Qing; Longnecker, Richard; Connolly, Sarah A (2014) Substitution of herpes simplex virus 1 entry glycoproteins with those of saimiriine herpesvirus 1 reveals a gD-gH/gL functional interaction and a region within the gD profusion domain that is critical for fusion. J Virol 88:6470-82
Möhl, Britta S; Sathiyamoorthy, Karthik; Jardetzky, Theodore S et al. (2014) The conserved disulfide bond within domain II of Epstein-Barr virus gH has divergent roles in membrane fusion with epithelial cells and B cells. J Virol 88:13570-9
Garcia, Nicholas J; Chen, Jia; Longnecker, Richard (2013) Modulation of Epstein-Barr virus glycoprotein B (gB) fusion activity by the gB cytoplasmic tail domain. MBio 4:e00571-12

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