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)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA117794-08
Application #
8519327
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Daschner, Phillip J
Project Start
2005-08-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$311,336
Indirect Cost
$56,970
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Chen, Jia; Sathiyamoorthy, Karthik; Zhang, Xianming et al. (2018) Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus. Nat Microbiol 3:172-180
Möhl, Britta S; Chen, Jia; Park, Seo Jin et al. (2017) Epstein-Barr Virus Fusion with Epithelial Cells Triggered by gB Is Restricted by a gL Glycosylation Site. J Virol 91:
Sathiyamoorthy, Karthik; Jiang, Jiansen; Möhl, Britta S et al. (2017) Inhibition of EBV-mediated membrane fusion by anti-gHgL antibodies. Proc Natl Acad Sci U S A 114:E8703-E8710
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
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
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; 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
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:
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
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

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