Ocular HSV infection is the leading cause of viral induced corneal blindness in the US. Genital HSV clinical trials using live attenuated virus or subunit vaccines given parenterally with powerful adjuvants showed poor efficacy. Rather than abandon all attempts to develop a successful ocular herpes vaccine, we think that the better response is to try to gain a better understanding of protective immunity against HSV and to develop novel, more immunogenic approaches. In particular, lipopeptide-based vaccines, which have recently gained considerable interest, represent a promising novel approach. We hypothesize that lipopeptide constructs containing critical HSV T-cell epitopes will induce powerful local cellular mucosal immune responses when delivered ocularly. This may ultimately prove to be a powerful approach for the development of a useful vaccine against ocular HSV.
Our Specific Aims i nclude: (1) Defining immuno-dominant CD4+ helper T cell (HTL) and CD8+ cytotoxic T cell (CTL) epitopes of HSV-1 glycoproteins gB & gD. Computer predicted human leukocyte antigen (HLA) restricted peptide epitopes will be examined for (a) high affinity binding to HLA molecules; (b) T-cell antigenicity using HLA phenotyped PBMC from both seropositive and seronegative donors; and (c) T-cell immunogenicity in HLA class I and II transgenic mice (i.e., mice that simulate the human immune system). (2) Construction and immunogenicity studies of lipopeptides using the epitopes determined in Specific Aim #1. Lipopeptides containing the """"""""best"""""""" CTL and HTL epitopes will be tested for induction of a broad based immune response using in vitro killing of HSV infected human dendritic cells (DC) and IFN-gamma ELISPOT assays. Protection against ocular HSV-1 challenge will be evaluated in HLA class I and class II transgenic mice models. (3) Optimize mucosal delivery of lipopeptides to the local ocular/mucosal immune system to determine if powerful mucosal immunity can be achieved at the eye. The use of different lipid moieties, and ocular vs. intranasal immunization will be explored to find the most efficacious way to provoke ocular mucosal immunity. Lipopeptides will be compared to peptide + mucosal adjuvant. Uptake and functional presentation of lipopeptide epitopes by DC to T-cells and subsequent DC maturation will be examined.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014900-04
Application #
7112257
Study Section
Special Emphasis Panel (ZRG1-VISA (01))
Program Officer
Shen, Grace L
Project Start
2003-09-30
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2006
Total Cost
$297,833
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
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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
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
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 90:5886-5898
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 90:3913-3928
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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
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
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

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