Herpes simplex virus (HSV-1) is a major cause of vision loss worldwide. The long term goal of this competitive renewal application is to develop an effective vaccine that will produce protective immunity against ocular herpes. Natural HSV-1 immunity does not efficiently protect against recurrent infections or new infections, suggesting that an effective vaccine will have to induce different and/or more vigorous immune responses than the sub-optimal natural immunity. The research in this application will specifically focus on: (1) Identifying human HSV-1 epitopes recognized by CD4+ and CD8+ T cells from individuals with high (symptomatic) and no (asymptomatic) recurrent herpes disease. (2) Using asymptomatic epitopes only to design a powerful "protective" T cell based herpes vaccine. During the initial funding cycle (2003-2009) and one year of ARRA funding (2009-2010), we have discovered that some HSV-1 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). Lack of strong response is not due to clonal deletion of an epitope specific TCR, since the response is not missing, it is just much lower. 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 a 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. Besides, gB and gD, HSV-1 tegument proteins VP11/12 and VP13/14 are also major targets for effector T cells. These intriguing results, together with relate reports by others in the field, lead us to hypothesize that: (1) Some HSV-1 epitopes are recognized differently by T cells from symptomatic compared to asymptomatic individuals. (2) Some epitopes recognized only by T cells from symptomatic individuals are pathogenic ("symptomatic epitopes");whereas some epitopes recognized only by T cells from asymptomatic individuals are protective ("asymptomatic epitopes").
Our Specific Aims i nclude:
Aim 1 : Test the hypothesis that, although most HSV-1 epitopes are recognized by both asymptomatic and symptomatic patients, there are human CD4+ and CD8+ T cell epitopes from gB, gD, VP11/12 and VP13/14 that are strongly recognized only by asymptomatic patients or only by symptomatic patients;
Aim 2 : Test the hypothesis that immunization with a combination of multiple "asymptomatic" epitopes from gB, gD, VP11/12 and VP13/14, will increase the magnitude, breadth and duration of T-cell protective immunity. A vaccine that incorporates only asymptomatic HSV-1 human T-cell epitopes and excludes symptomatic epitopes 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.

Public Health Relevance

Over 100 million individuals in the US are infected by HSV-1 and approximately 450,000 adults have a history of recurrent ocular disease that can cause loss of vision. This competitive renewal application for an R01 research grant is to identify epitopes specifically recognized by CD4+ and CD8+ T cells from individuals with high (symptomatic) and low (asymptomatic) recurrent ocular herpes disease. The information will be used to design a powerful T cell-based lipopeptide vaccine against ocular herpes.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Schools of Medicine
United States
Zip Code
Farid, Marjan; Agrawal, Anshu; Fremgen, Daniel et al. (2015) Age-related Defects in Ocular and Nasal Mucosal Immune System and the Immunopathology of Dry Eye Disease. Ocul Immunol Inflamm :21-Jan
Richichi, Barbara; Thomas, Baptiste; Fiore, Michele et al. (2014) A cancer therapeutic vaccine based on clustered Tn-antigen mimetics induces strong antibody-mediated protective immunity. Angew Chem Int Ed Engl 53:11917-20
Samandary, Sarah; Kridane-Miledi, Hédia; Sandoval, Jacqueline S et al. (2014) Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: implication for the development of an universal CD8+ T-cell epitope-based vaccine. Hum Immunol 75:715-29
Planès, Rémi; BenMohamed, Lbachir; Leghmari, Kaoutar et al. (2014) HIV-1 Tat protein induces PD-L1 (B7-H1) expression on dendritic cells through tumor necrosis factor alpha- and toll-like receptor 4-mediated mechanisms. J Virol 88:6672-89
Dec, Eric; Rana, Prachi; Katheria, Veeral et al. (2014) Cytokine profiling in patients with VCP-associated disease. Clin Transl Sci 7:29-32
Khan, Arif Azam; Srivastava, Ruchi; Lopes, Patricia Prado et al. (2014) Asymptomatic memory CD8+ T cells: from development and regulation to consideration for human vaccines and immunotherapeutics. Hum Vaccin Immunother 10:945-63
Kuo, Tiffany; Wang, Christine; Badakhshan, Tina et al. (2014) The challenges and opportunities for the development of a T-cell epitope-based herpes simplex vaccine. Vaccine 32:6733-45
Prakash, S; Agrawal, S; Vahed, H et al. (2014) Dendritic cells from aged subjects contribute to chronic airway inflammation by activating bronchial epithelial cells under steady state. Mucosal Immunol 7:1386-94
Dasgupta, Gargi; Chentoufi, Aziz A; Kalantari, Mina et al. (2012) Immunodominant "asymptomatic" herpes simplex virus 1 and 2 protein antigens identified by probing whole-ORFome microarrays with serum antibodies from seropositive asymptomatic versus symptomatic individuals. J Virol 86:4358-69
Chentoufi, Aziz Alami; Dervillez, Xavier; Dasgupta, Gargi et al. (2012) The herpes simplex virus type 1 latency-associated transcript inhibits phenotypic and functional maturation of dendritic cells. Viral Immunol 25:204-15

Showing the most recent 10 out of 36 publications