This proposal represents a new research direction on HCMV entry glycoproteins for the Jardetzky Laboratory, which has previously had extensive prior effort focusing on understanding Epstein-Barr virus (EBV) entry into target cells and on developing novel approaches to therapeutic intervention. The entry of HCMV into epithelial and endothelial cells requires the formation of a pentameric viral glycoprotein complex comprised of the gH, gL, UL128, UL130, and UL131 proteins (gHgL/UL128-131). This pentameric complex is a functional analog of the EBV gHgL/gp42 complex, which targets EBV to infect B cells. HCMV gHgL also assembles into a trimeric complex with the gO protein, which has a broader functional role, affecting virus entry into fibroblasts, epithelial cells and endothelial cells. Th Jardetzky Laboratory has conducted extensive crystallographic and functional studies of the EBV gHgL and gp42 complexes and demonstrated that EBV infection can be blocked with a gp42-derived high affinity peptide inhibitor. We now propose to conduct similar studies of the HCMV gHgL, gHgL/gO and gHgL/UL128-131 complexes, as well as examine the interaction of HCMV gHgL complexes with neutralizing antibodies. These studies will further our understanding of herpesvirus entry mechanisms and may lead to new routes to developing HCMV entry inhibitors or gHgL subunit vaccines.

Public Health Relevance

This proposed research represents a new research effort by the Jardetzky Laboratory to define the molecular mechanisms involved in Human Cytomegalovirus (HCMV) infection mechanisms, focusing on the viral gHgL glycoprotein and its associated complexes. Dr. Jardetzky's previous experience in investigating analogous mechanisms of EBV entry into B cells and epithelial cells will be used to develop new approaches for HCMV studies. The proposed research will lead to new insights into the HCMV entry into cells and the neutralization of gHgL complexes by human antibodies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI103722-01A1
Application #
8702328
Study Section
Virology - A Study Section (VIRA)
Program Officer
Beisel, Christopher E
Project Start
2014-02-13
Project End
2016-01-31
Budget Start
2014-02-13
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$240,750
Indirect Cost
$90,750
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305