Herpes simplex viruses (HSV) can spread very efficiently directly from one cell to a neighboring cell, in epithelial and neuronal tissues. The property appears to involve transport of virus particles across cell junctions or contacts made between cells. Viral glycoproteins gE and gI are necessary for efficient spread of HSV between cells but are not required for entry of extracellular virus. Therefore, HSV gE and gI and homologues in other herpesviruses appear to selectively act in cell-to- cell spread and not at the cell surface during entry of extracellular viruses. This the only example of proteins which function in this manner. gE/gI has also been ascribed an IgG-Fc receptor activity, but this property appears to be unrelated to the capacity to facilitate cell-to-cell transmission. We have found that gE/gI localizes specifically to the lateal surfaces of epithelial cells, colocalizing with adherens junctions and being excluded from tight junctions, and is not present on those lateral surfaces of cells not in contact with other cells. This suggests that gE/gI has the capacity to bind to cell junction components so that accumulation at cell junctions occurs. It is my hypothesis that gE/gI binds to cellular ligands concentrated at cell junctions to promote transfer of virus between cells. The objectives of this research are to examine the molecular mechanisms by which HSV spreads from cell-to-cell. We will study the relationship between cell-cell spread and accumulation of gE/gI at cell junctions, whether gE/gI expressed in cells can saturate cell ligands and block cell-cell spread, the role of various cell junction components and cell adhesion molecules (CAMs) in this process, and attempt to identify cellular ligands of gE/gI. These studies should shed light not only on how this virus interacts with cell junctions but also provide valuable new information on the cell biology of cell junctions. The integrity of cell junctions is important to maintain a permeability barrier and also so that the normal course of differentiation and growth regulation are maintained. Loss of CAMs or CAM adaptors occurs during progression to a more malignant phenotype. CAMs or CAM adaptors, e.g. APC, DCC, and cadherins, are known to act as tumor suppressors and their loss leads to a less differentiated and more motile or metastatic phenotype. I expect that our studies of the interactions between HSV and cell junctions will have significance, providing new information on the relationship between specific CAMs and virus spread and a better understanding of how CAMs function in cells and tissues.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073996-05
Application #
6513067
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Wong, May
Project Start
1998-07-01
Project End
2003-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
5
Fiscal Year
2002
Total Cost
$239,568
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Farnsworth, Aaron; Goldsmith, Kimberly; Johnson, David C (2003) Herpes simplex virus glycoproteins gD and gE/gI serve essential but redundant functions during acquisition of the virion envelope in the cytoplasm. J Virol 77:8481-94
Collins, Wendy J; Johnson, David C (2003) Herpes simplex virus gE/gI expressed in epithelial cells interferes with cell-to-cell spread. J Virol 77:2686-95
Hegde, Nagendra R; Chevalier, Mathieu S; Johnson, David C (2003) Viral inhibition of MHC class II antigen presentation. Trends Immunol 24:278-85
Chevalier, Mathieu S; Johnson, David C (2003) Human cytomegalovirus US3 chimeras containing US2 cytosolic residues acquire major histocompatibility class I and II protein degradation properties. J Virol 77:4731-8
Hegde, Nagendra R; Johnson, David C (2003) Human cytomegalovirus US2 causes similar effects on both major histocompatibility complex class I and II proteins in epithelial and glial cells. J Virol 77:9287-94
Chevalier, Mathieu S; Daniels, Gwynn M; Johnson, David C (2002) Binding of human cytomegalovirus US2 to major histocompatibility complex class I and II proteins is not sufficient for their degradation. J Virol 76:8265-75
Johnson, David C; Huber, Mary T (2002) Directed egress of animal viruses promotes cell-to-cell spread. J Virol 76:1-8
Huber, Mary T; Tomazin, Roman; Wisner, Todd et al. (2002) Human cytomegalovirus US7, US8, US9, and US10 are cytoplasmic glycoproteins, not found at cell surfaces, and US9 does not mediate cell-to-cell spread. J Virol 76:5748-58
Trgovcich, Joanne; Johnson, David; Roizman, Bernard (2002) Cell surface major histocompatibility complex class II proteins are regulated by the products of the gamma(1)34.5 and U(L)41 genes of herpes simplex virus 1. J Virol 76:6974-86
McMillan, T N; Johnson, D C (2001) Cytoplasmic domain of herpes simplex virus gE causes accumulation in the trans-Golgi network, a site of virus envelopment and sorting of virions to cell junctions. J Virol 75:1928-40

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