Effective host defense against viral pathogens requires antigen-receptor activation and cooperating signaling (cosignaling) from cell surface molecules and cytokines. The herpesvirus entry mediator (HVEM;TNFRSF14), a member of the TNF Receptor superfamily, serves as a molecular switch between proinflammatory and inhibitory cosignaling pathways initiated by coreceptors, LIGHT (TNFSF14) and the immunoglobulin superfamily member BTLA (B and T lymphocyte attenuator). New results indicate effective memory T cell differentiation requires the HVEM cosignaling system, however, viral pathogens usurp the HVEM pathway to thwart effective host defense. This project focuses on the HVEM system in viral latency. We recently discovered that Herpes Simplex virus (HSV)-1 requires LIGHT-HVEM-BTLA system to maintain latency in the trigeminal ganglia in a mouse ocular infection model. Our preliminary evidence indicates that HSV-1 is unable to efficiently maintain latency in mice genetically deficient in HVEM, BTLA or LIGHT and the viral latency- associated transcript (LAT) uniquely upregulates HVEM expression in latently infected ganglia. Moreover, effector T cells fail to accumulate in the ganglia during latent infection in mice lacking HVEM or HSV deficient in LAT. These results implicate multiple roles for the HVEM cosignaling pathway in HSV-1 infected neurons and in effector T cells controlling latency. We have recruited key collaborators and developed animal and tissue culture models that can be probed using genetic and biochemical approaches to investigate the HVEM cosignaling pathway in viral latency. To accomplish this goal we propose two specific aims: 1) characterize molecular interactions regulating the expression and cosignaling actions of HVEM and its ligands in neuronal and T cell lines, and 2) investigate the requirement of HVEM signaling in vivo in neuronal and lymphoid compartments in latency. This investigation will provide new insight into the mechanisms of the HVEM cosignaling system in regulating viral pathogenesis.

Public Health Relevance

Some viruses can hide to escape from elimination by the immune response. In this project we study how a common virus, Herpes Simplex virus, uses the immune system to maintain itself in a hidden (latent) state. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067890-08
Application #
8716640
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Dong, Gang
Project Start
2005-12-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Allen, Sariah J; Rhode-Kurnow, Antje; Mott, Kevin R et al. (2014) Interactions between herpesvirus entry mediator (TNFRSF14) and latency-associated transcript during herpes simplex virus 1 latency. J Virol 88:1961-71
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Flynn, Rachel; Hutchinson, Tarun; Murphy, Kenneth M et al. (2013) CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA. PLoS One 8:e77991
Bjordahl, Ryan L; Steidl, Christian; Gascoyne, Randy D et al. (2013) Lymphotoxin network pathways shape the tumor microenvironment. Curr Opin Immunol 25:222-9

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