This application proposes to examine the role of the HSV IgG Fc receptor (FcR) in immune evasion. HSV glycoproteins gE and gI form the FcR, which binds the Fc domain of human anti-HSV antibodies blocking Fc-mediated functions including complement activation and antibody-dependent cellular cytotoxicity. The goals are: (1) to construct and characterize gE and gI mutant viruses with mutations in the Fc binding regions. The mutants will be assessed for FcR activity, spread in cell culture, and transneuronal spread in a mouse eye model. (2) Mutants defective in FcR activity but intact for cell spread will be used to define the biological relevance of the HSV-1 FcR in vivo. The mutants will be tested for their ability to cause disease at the site of inoculation and via zosteriform spread in a mouse flank model. The importance of the FcR in viral pathogenesis will be assessed by passive transfer of either human or murine IgG to animals inoculated with FcR+ or FcR-viruses. The hypothesis to be tested is that human IgG will be more active against FcR- than FcR+ viruses because the IgG Fc-domain is available to activate complement and mediate ADCC. (3) The investigators propose to try and block HSV FcR-mediated immune evasion by immunizing with gE or gI. Candidate gE and gI immunogens include full length and secreted forms of gE and gI, and peptides or fusion proteins that target specific Fc binding domains. If antibodies to these immunogens block FcR activity, the immunogens will be added to a gD vaccine to determine if the combination improves efficacy. The investigators suggest these studies will address mechanisms of HSV immune evasion and may result in novel strategies for the development of subunit HSV vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033063-09
Application #
6373284
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Beisel, Christopher E
Project Start
1992-07-01
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
9
Fiscal Year
2001
Total Cost
$226,280
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Awasthi, Sita; Zumbrun, Elizabeth E; Si, Huaxin et al. (2012) Live attenuated herpes simplex virus 2 glycoprotein E deletion mutant as a vaccine candidate defective in neuronal spread. J Virol 86:4586-98
Lubinski, John M; Lazear, Helen M; Awasthi, Sita et al. (2011) The herpes simplex virus 1 IgG fc receptor blocks antibody-mediated complement activation and antibody-dependent cellular cytotoxicity in vivo. J Virol 85:3239-49
Haugo, Alison C; Szpara, Moriah L; Parsons, Lance et al. (2011) Herpes simplex virus 1 pUL34 plays a critical role in cell-to-cell spread of virus in addition to its role in virus replication. J Virol 85:7203-15
Szpara, Moriah L; Tafuri, Yolanda R; Parsons, Lance et al. (2011) A wide extent of inter-strain diversity in virulent and vaccine strains of alphaherpesviruses. PLoS Pathog 7:e1002282
Huang, Jialing; Lazear, Helen M; Friedman, Harvey M (2011) Completely assembled virus particles detected by transmission electron microscopy in proximal and mid-axons of neurons infected with herpes simplex virus type 1, herpes simplex virus type 2 and pseudorabies virus. Virology 409:12-6
Wang, Fushan; Zumbrun, Elizabeth E; Huang, Jialing et al. (2010) Herpes simplex virus type 2 glycoprotein E is required for efficient virus spread from epithelial cells to neurons and for targeting viral proteins from the neuron cell body into axons. Virology 405:269-79
Szpara, Moriah L; Parsons, Lance; Enquist, L W (2010) Sequence variability in clinical and laboratory isolates of herpes simplex virus 1 reveals new mutations. J Virol 84:5303-13
McGraw, Helen M; Awasthi, Sita; Wojcechowskyj, Jason A et al. (2009) Anterograde spread of herpes simplex virus type 1 requires glycoprotein E and glycoprotein I but not Us9. J Virol 83:8315-26
King, Ryan D; Lubinski, John M; Friedman, Harvey M (2009) Herpes simplex virus type 1 infection increases the carbohydrate binding activity and the secretion of cellular galectin-3. Arch Virol 154:609-18
McGraw, Helen M; Friedman, Harvey M (2009) Herpes simplex virus type 1 glycoprotein E mediates retrograde spread from epithelial cells to neurites. J Virol 83:4791-9

Showing the most recent 10 out of 16 publications