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. !

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Dong, Gang
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sanford-Burnham Medical Research Institute
La Jolla
United States
Zip Code
Correa, Ricardo G; Krajewska, Maryla; Ware, Carl F et al. (2014) The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling. Oncotarget 5:1666-82
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
Bekiaris, Vasileios; Sedy, John R; Rossetti, Maura et al. (2013) Human CD4+CD3- innate-like T cells provide a source of TNF and lymphotoxin-** and are elevated in rheumatoid arthritis. J Immunol 191:4611-8
Bekiaris, Vasileios; Sedý, John R; Macauley, Matthew G et al. (2013) The inhibitory receptor BTLA controls ?? T cell homeostasis and inflammatory responses. Immunity 39:1082-94
Doherty, Taylor A; Soroosh, Pejman; Khorram, Naseem et al. (2011) The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nat Med 17:596-603
Sato-Hashimoto, Miho; Saito, Yasuyuki; Ohnishi, Hiroshi et al. (2011) Signal regulatory protein ýý regulates the homeostasis of T lymphocytes in the spleen. J Immunol 187:291-7
Cheung, Timothy C; Ware, Carl F (2011) The canonical and unconventional ligands of the herpesvirus entry mediator. Adv Exp Med Biol 691:353-62
Steinberg, Marcos W; Cheung, Timothy C; Ware, Carl F (2011) The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunol Rev 244:169-87
Ware, Carl F; Sedy, John R (2011) TNF Superfamily Networks: bidirectional and interference pathways of the herpesvirus entry mediator (TNFSF14). Curr Opin Immunol 23:627-31
Soroosh, Pejman; Doherty, Taylor A; So, Takanori et al. (2011) Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations. J Exp Med 208:797-809

Showing the most recent 10 out of 18 publications