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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA117794-09
Application #
8676684
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Daschner, Phillip J
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
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
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
Rowe, Cynthia L; Connolly, Sarah A; Chen, Jia et al. (2013) A soluble form of Epstein-Barr virus gH/gL inhibits EBV-induced membrane fusion and does not function in fusion. Virology 436:118-26
Chen, Jia; Jardetzky, Theodore S; Longnecker, Richard (2013) The large groove found in the gH/gL structure is an important functional domain for Epstein-Barr virus fusion. J Virol 87:3620-7
Chen, Jia; Rowe, Cynthia L; Jardetzky, Theodore S et al. (2012) The KGD motif of Epstein-Barr virus gH/gL is bifunctional, orchestrating infection of B cells and epithelial cells. MBio 3:
Connolly, Sarah A; Jackson, Julia O; Jardetzky, Theodore S et al. (2011) Fusing structure and function: a structural view of the herpesvirus entry machinery. Nat Rev Microbiol 9:369-81
Plate, Aileen E; Reimer, Jessica J; Jardetzky, Theodore S et al. (2011) Mapping regions of Epstein-Barr virus (EBV) glycoprotein B (gB) important for fusion function with gH/gL. Virology 413:26-38
Rowe, Cynthia L; Matsuura, Hisae; Jardetzky, Theodore S et al. (2011) Investigation of the function of the putative self-association site of Epstein-Barr virus (EBV) glycoprotein 42 (gp42). Virology 415:122-31

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