Cytotoxic T lymphocytes (CTL) can protect against HeCrpes simplex virus type 1 (HSV-1) infections by destroying infected cells (cytotoxicity) or by inhibiting virus replication through the elaboration of antiviral cytokines. Studies during the current funding period established that both the host and the virus have developed tissue-specific mechanisms to regulate CTL function. We will now further define these regulatory mechanisms.
Specific aims 1 and 2 will investigate a novel regulatory circuit in the cornea that controls CTL functions. Corneal fibroblasts, upon exposure to a soluble factor from HSV-1 infected normal spleen cells, strongly induce the production of the antiviral cytokine interferon (IFN)-gamma, while actively inhibiting their proliferation and differentiation into cytotoxic effector cells.
Specific aim 1 is to define the mechanism by which corneal fibroblasts inhibit CTL precursor proliferation and acquisition of cytotoxic function. We will determine the effect of corneal fibroblasts: 1) on early and late T cell receptor (TCR) signaling events in CTL precursors; 2) on the capacity on CTL precursors to produce the lytic granules that mediate target cell destruction, and their ability to exocytose these granules upon TCR stimulation; and 3) on the ability of the CTL to bind to the target cells and to express the adhesion molecules that facilitate this binding. Studies in specific aim 2 will determine the source and identity of the inhibitory factor that regulates CTL precursor activation by corneal fibroblasts.
Specific aim 3 is to further our studies of HSV immune evasion mechanisms. We have established that the HSV-1 US12 gene product, ICP47 can augment HSV-1 neurovirulence in mice by inhibiting a protective CTL response. We will now pursue our suggestive evidence that the closely linked US11 gene product can serve a similar function. These studies will utilize HSV-1 US11 deletion mutants, US11/US12 double deletion mutants, and their revertants. We will employ both in vivo and in vitro studies to investigate the effect of the US11 and US12 gene products on CTL control of HSV-1 replication in the trigeminal ganglia and brains of infected mice. By providing a better understanding of the complex interaction among HSV-1, specific host tissues, and CTL we hope to devise new strategies to provide optimal host protection, with minimal immunopathology.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005945-17
Application #
6627008
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Shen, Grace L
Project Start
1986-09-30
Project End
2003-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
17
Fiscal Year
2003
Total Cost
$336,885
Indirect Cost
Name
University of Pittsburgh
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jeon, Sohyun; Rowe, Alexander M; Carroll, Kate L et al. (2018) PD-L1/B7-H1 Inhibits Viral Clearance by Macrophages in HSV-1-Infected Corneas. J Immunol 200:3711-3719
Rowe, Alexander M; Yun, Hongmin; Hendricks, Robert L (2017) Exposure Stress Induces Reversible Corneal Graft Opacity in Recipients With Herpes Simplex Virus-1 Infections. Invest Ophthalmol Vis Sci 58:35-41
Rowe, Alexander M; Yun, Hongming; Treat, Benjamin R et al. (2017) Subclinical Herpes Simplex Virus Type 1 Infections Provide Site-Specific Resistance to an Unrelated Pathogen. J Immunol 198:1706-1717
Yun, Hongmin; Lathrop, Kira L; Hendricks, Robert L (2016) A Central Role for Sympathetic Nerves in Herpes Stromal Keratitis in Mice. Invest Ophthalmol Vis Sci 57:1749-56
Kuffova, Lucia; Knickelbein, Jared E; Yu, Tian et al. (2016) High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection. Invest Ophthalmol Vis Sci 57:1578-87
Buela, Kristine-Ann G; Hendricks, Robert L (2015) Cornea-infiltrating and lymph node dendritic cells contribute to CD4+ T cell expansion after herpes simplex virus-1 ocular infection. J Immunol 194:379-87
Jeon, Sohyun; St Leger, Anthony J; Cherpes, Thomas L et al. (2013) PD-L1/B7-H1 regulates the survival but not the function of CD8+ T cells in herpes simplex virus type 1 latently infected trigeminal ganglia. J Immunol 190:6277-86
St Leger, Anthony J; Jeon, Sohyun; Hendricks, Robert L (2013) Broadening the repertoire of functional herpes simplex virus type 1-specific CD8+ T cells reduces viral reactivation from latency in sensory ganglia. J Immunol 191:2258-65
Rowe, A M; St Leger, A J; Jeon, S et al. (2013) Herpes keratitis. Prog Retin Eye Res 32:88-101
Kinchington, Paul R; Leger, Anthony J St; Guedon, Jean-Marc G et al. (2012) Herpes simplex virus and varicella zoster virus, the house guests who never leave. Herpesviridae 3:5

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