Viruses require live cells to replicate; consequently, the physiological regulation of cell death is a potential potent means of influencing viral production during an infection. An important mechanism for the induction of apoptosis involves the cell surface protein Fas ligand on one cell binding to another cell surface protein, Fas, on another cell. This interaction induces the Fas-bearing cell to initiate the apoptotic pathway by inducing the expression of Fas in the infected cells. One powerful and responsible measure of the importance of a particular anti-viral immune mechanism is the emphasis viruses have put on thwarting that immune mechanism. We have found the herpes simplex virus type (HSV-2) has the capacity to inhibit the surface expression Fas ligand thereby inhibit Fas ligand activity. HSV-1 also inhibits Fas ligand activity, however, to a lesser capacity compared to HSV-2. We have used HSV-1 x HSV-2 recombinants and a deletion mutant to map the function of Fas ligand inhibition to the U/s 3 gene of the virus, which encodes for the protein kinase (PK) of alpha herpesviruses. In this grant application we have proposed experiments that address whether HSV-PK is sufficient to mediate Fas ligand inhibition, the sub- cellular localization of Fas ligand in cells infected with HSV, and the role of the kinase activity of PK in mediating this effect. Furthermore, we propose to assess the part that PK and its inhibition of Fas ligand may play in murine models of HSV infections focusing on the effects involving the Fas/Fas ligand apoptotic pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077428-05
Application #
6633300
Study Section
Special Emphasis Panel (ZRG1-EVR (02))
Program Officer
Wong, May
Project Start
1999-07-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2005-04-30
Support Year
5
Fiscal Year
2003
Total Cost
$296,910
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Kaplan, David; Meyerson, Howard; Husel, William et al. (2005) D cyclins in lymphocytes. Cytometry A 63:1-9
Lewandowska, Kristine; Kaplan, David; Husel, William (2003) CD34 expression on platelets. Platelets 14:83-7
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Kaplan, D; Smith, D; Meyerson, H et al. (2001) CD5 expression by B lymphocytes and its regulation upon Epstein-Barr virus transformation. Proc Natl Acad Sci U S A 98:13850-3