This proposal is submitted in response to RFA HL-02-002. Like murine CMV, y,HV68 causes chronic vasculitis restricted to the great elastic arteries (elastic arteritis). The major findings from years 1-3 of RO1 HL60090 relevant to this proposal were that: (i) persistent viral replication in the smooth muscle cells of the media of the great elastic arteries is responsible for arteritis, (ii) the media of the great elastic arteries is an immunoprivileged site, (iii) the yHV68 v-cyclin and v-bcl-2 are important for induction of arteritis, and iv) IFN,/and likely CD4 T cells protect against virus induced arteritis. To determine whether viral injury triggers atherosclerosis, we performed preliminary studies and discovered that 7HV68 triggers atherosclerosis in apoE-/- mice. In this proposal we test the hypothesis, based on our data and data in the literature, that the viral and immune mechanisms that regulate elastic arteritis are the same as those that regulate virus induced atherosclerosis. The progress made during the first 3 years of R01HL60090, and new preliminary data, will allow us to define mechanisms responsible for induction of and protection against elastic arteritis and the relationship between virus induced arteritis, immunity, and development of atherosclerosis* via the following Aims.
Aim 1. Determine the role of T cells in virus induced elastic arteritis Aim 2. Characterize the pathogenesis of virus induced atherosclerosis* in apoE-/- mice Aim 3. Identify the immune mechanisms that protect against or enhance vires induced atherosclerosis* By performing these studies we hope to define immune and viral mechanisms that operate to protect or to damage the great vessels, and to determine the relationship between these mechanisms and the development of atherosclerosis. This will allow us to manipulate the immune system to prevent atherosclerosis induction by virus infection, and potentially to vaccinate against virus induced atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060090-07
Application #
6793117
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Program Officer
Tolunay, Eser
Project Start
1998-12-15
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
7
Fiscal Year
2004
Total Cost
$382,500
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Steed, Ashley L; Barton, Erik S; Tibbetts, Scott A et al. (2006) Gamma interferon blocks gammaherpesvirus reactivation from latency. J Virol 80:192-200
McClellan, Kelly B; Gangappa, Shivaprakash; Speck, Samuel H et al. (2006) Antibody-independent control of gamma-herpesvirus latency via B cell induction of anti-viral T cell responses. PLoS Pathog 2:e58
Sparks-Thissen, Rebecca L; Braaten, Douglas C; Hildner, Kai et al. (2005) CD4 T cell control of acute and latent murine gammaherpesvirus infection requires IFNgamma. Virology 338:201-8
Loh, Joy; Chu, Dortha T; O'Guin, Andrew K et al. (2005) Natural killer cells utilize both perforin and gamma interferon to regulate murine cytomegalovirus infection in the spleen and liver. J Virol 79:661-7
Virgin, Herbert W (2005) Immune regulation of viral infection and vice versa. Immunol Res 32:293-315
Barton, Erik S; Lutzke, Mary L; Rochford, Rosemary et al. (2005) Alpha/beta interferons regulate murine gammaherpesvirus latent gene expression and reactivation from latency. J Virol 79:14149-60
van Dyk, Linda F; Virgin 4th, Herbert W; Speck, Samuel H (2003) Maintenance of gammaherpesvirus latency requires viral cyclin in the absence of B lymphocytes. J Virol 77:5118-26
Tibbetts, Scott A; McClellan, J Scott; Gangappa, Shivaprakash et al. (2003) Effective vaccination against long-term gammaherpesvirus latency. J Virol 77:2522-9
Moorman, Nathaniel J; Virgin 4th, Herbert W; Speck, Samuel H (2003) Disruption of the gene encoding the gammaHV68 v-GPCR leads to decreased efficiency of reactivation from latency. Virology 307:179-90
Pavlova, Iglika V; Virgin 4th, Herbert W; Speck, Samuel H (2003) Disruption of gammaherpesvirus 68 gene 50 demonstrates that Rta is essential for virus replication. J Virol 77:5731-9

Showing the most recent 10 out of 23 publications