Herpes simplex virus (HSV-1) is a major cause of vision loss worldwide. Our long-term goal is to develop an effective vaccine against ocular herpes. We have discovered that some human HSV-1 glycoprotein B and D (gB and gD) epitopes were strongly recognized by CD4+ and CD8+ T cells from asymptomatic patients but not from symptomatic patients, while other gB and gD epitopes were strongly recognized by T-cells from symptomatic but not from asymptomatic patients (P<0.005). We obtained proof-of-principle that intranasal immunization of double transgenic mice expressing both class 1 and class 2 Human Leukocyte Antigens (i.e. HLA-DR and HLA-A2.1) with """"""""asymptomatic CD4+ and CD8+ peptide epitopes"""""""" linked to lipid moiety (lipopeptides), but not with """"""""symptomatic CD4+ and CD8+ peptide epitopes"""""""", induced strong local HSV-specific T cells and provided protection against ocular challenge with HSV-1. Herpes tegument proteins VP11/12 and VP13/14 are also major targets for effector T cells.
Our Specific Aim for year 1 is: Test the hypothesis that, although most HSV-1 epitopes are recognized by both asymptomatic and symptomatic patients, there are human gB, gD, VP11/12, and VP13/14 CD4+ and CD8+ T cell epitopes that are recognized only by asymptomatic patients or only by symptomatic patients. The identification and characterization of the spectrum of HSV-1 T cell epitopes recognized by asymptomatic and symptomatic patients is a novel approach that should break new ground in our understanding of the immune mechanisms underlying ocular herpes disease and may ultimately lead to an effective vaccine. This research is in accordance with the American Recovery and Reinvestment Act (ARRA) program. The proposal requests one-year funding support of the previously funded parent RO1 grant NEI 14900 """"""""Ocular Mucosal Immunity Induced by HSV-1 Lipopeptides"""""""".

Public Health Relevance

This project is aimed at developing a multi-valent self-adjuvanting lipopeptide vaccine against ocular herpes. This novel vaccine molecule is based on asymptomatic human CD4+ and CD8+ gB, gD, VP11/12 and VP13/14 T-cell epitopes linked to a palmitic acid CD4+ moiety, as built-in adjuvant.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY014900-06A2
Application #
7784165
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Shen, Grace L
Project Start
2003-09-30
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
6
Fiscal Year
2010
Total Cost
$382,500
Indirect Cost
Name
University of California Irvine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Khan, Arif A; Srivastava, Ruchi; Chentoufi, Aziz A et al. (2017) Bolstering the Number and Function of HSV-1-Specific CD8+ Effector Memory T Cells and Tissue-Resident Memory T Cells in Latently Infected Trigeminal Ganglia Reduces Recurrent Ocular Herpes Infection and Disease. J Immunol 199:186-203
Jiang, Xianzhi; Brown, Don; Osorio, Nelson et al. (2016) Increased neurovirulence and reactivation of the herpes simplex virus type 1 latency-associated transcript (LAT)-negative mutant dLAT2903 with a disrupted LAT miR-H2. J Neurovirol 22:38-49
Farid, Marjan; Agrawal, Anshu; Fremgen, Daniel et al. (2016) Age-related Defects in Ocular and Nasal Mucosal Immune System and the Immunopathology of Dry Eye Disease. Ocul Immunol Inflamm 24:327-47
Perng, Guey-Chuen; Osorio, Nelson; Jiang, Xianzhi et al. (2016) Large Amounts of Reactivated Virus in Tears Precedes Recurrent Herpes Stromal Keratitis in Stressed Rabbits Latently Infected with Herpes Simplex Virus. Curr Eye Res 41:284-91
Planès, Rémi; Ben Haij, Nawal; Leghmari, Kaoutar et al. (2016) HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes. J Virol 90:5886-98
Srivastava, Ruchi; Dervillez, Xavier; Khan, Arif A et al. (2016) The Herpes Simplex Virus Latency-Associated Transcript Gene Is Associated with a Broader Repertoire of Virus-Specific Exhausted CD8+ T Cells Retained within the Trigeminal Ganglia of Latently Infected HLA Transgenic Rabbits. J Virol 90:3913-28
BenMohamed, Lbachir; Osorio, Nelson; Khan, Arif A et al. (2016) Prior Corneal Scarification and Injection of Immune Serum are Not Required Before Ocular HSV-1 Infection for UV-B-Induced Virus Reactivation and Recurrent Herpetic Corneal Disease in Latently Infected Mice. Curr Eye Res 41:747-56
Jester, James V; Morishige, Naoyuki; BenMohamed, Lbachir et al. (2016) Confocal Microscopic Analysis of a Rabbit Eye Model of High-Incidence Recurrent Herpes Stromal Keratitis. Cornea 35:81-8
Ben Haij, Nawal; Planès, Rémi; Leghmari, Kaoutar et al. (2015) HIV-1 Tat Protein Induces Production of Proinflammatory Cytokines by Human Dendritic Cells and Monocytes/Macrophages through Engagement of TLR4-MD2-CD14 Complex and Activation of NF-?B Pathway. PLoS One 10:e0129425
Khan, Arif A; Srivastava, Ruchi; Chentoufi, Aziz A et al. (2015) Therapeutic immunization with a mixture of herpes simplex virus 1 glycoprotein D-derived “asymptomatic” human CD8+ T-cell epitopes decreases spontaneous ocular shedding in latently infected HLA transgenic rabbits: association with low frequency of local P J Virol 89:6619-32

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