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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Shen, Grace L
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University of California Irvine
Schools of Medicine
United States
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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
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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
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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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