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)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Dong, Gang
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Desai, Pritesh; Tahiliani, Vikas; Hutchinson, Tarun E et al. (2018) The TNF Superfamily Molecule LIGHT Promotes the Generation of Circulating and Lung-Resident Memory CD8 T Cells following an Acute Respiratory Virus Infection. J Immunol 200:2894-2904
Desai, Pritesh; Abboud, Georges; Stanfield, Jessica et al. (2017) HVEM Imprints Memory Potential on Effector CD8 T Cells Required for Protective Mucosal Immunity. J Immunol 199:2968-2975
Šedý, John R; Balmert, M Olivia; Ware, Brian C et al. (2017) A herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor B and T lymphocyte attenuator. J Biol Chem 292:21060-21070
Ward-Kavanagh, Lindsay K; Lin, Wai Wai; Šedý, John R et al. (2016) The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity 44:1005-19
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; Šedý, John R; Ware, Carl F (2014) Mixing Signals: Molecular Turn Ons and Turn Offs for Innate ?? T-Cells. Front Immunol 5:654
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
Ware, Carl F (2013) Protein therapeutics targeted at the TNF superfamily. Adv Pharmacol 66:51-80
Šedý, John R; Bjordahl, Ryan L; Bekiaris, Vasileios et al. (2013) CD160 activation by herpesvirus entry mediator augments inflammatory cytokine production and cytolytic function by NK cells. J Immunol 191:828-36
Bekiaris, Vasileios; Šedý, John R; Macauley, Matthew G et al. (2013) The inhibitory receptor BTLA controls ?? T cell homeostasis and inflammatory responses. Immunity 39:1082-1094

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