Recurrent ocular herpetic disease, a major cause of vision loss worldwide, occurs following reactivation of latent herpes simplex virus (HSV-1) from sensory neurons of the trigeminal ganglia (TG). Our long-term goal is to develop a safe and efficient immunotherapeutic vaccine to stop virus reactivation and shedding in tears. While HSV-specific CD8+ T cells are critical in reducing virus reactivations, they also appear to be associated with the immuno-pathology that leads to corneal herpetic lesions. During the last 5 years, we have made several significant findings that form the basis of this competitive renewal application: (1) HSV-specific memory CD8+ T cells from naturally protected seropositive asymptomatic (ASYMP) individuals (those who are infected but never develop recurrent ocular herpes) are mainly effector memory T cells (TEM cells). In contrast, HSV-specific memory CD8+ T cells from symptomatic (SYMP) patients (those who often develop recurrent ocular herpes) are mainly central memory T cells (TCM cells). (2) CD8+ T cells from ASYMP individuals, but not CD8+ T-cells from SYMP individuals, strongly recognize distinct and non-overlapping sets of epitopes from HSV-1 glycoproteins and tegument proteins, and vice versa. (3) Therapeutic immunization of latently infected HLA Tg rabbits with HSV-1 ASYMP CD8+ T cell epitopes boosted the number and function of HSV-specific CD8+ TEM and tissue- resident memory CD8 T cells (TRM cells) in TG and decreased spontaneous viral shedding in tears. (4) A significant proportion of CD8+ T cells in TG of non-protected HLA Tg rabbits expressed high levels of PD-1 and CTLA-4 inhibitory receptors and appeared to be dysfunctional. (5) Topical ocular application of an AAV8 vector expressing the T-cell attracting chemokine CXCL10 pulled more CD8+ TEM and tissue-resident memory T cells (TRM cells) into TG of HSV-1 latently infected HLA Tg rabbits and reduced virus shedding in tears. Building on these strong published and preliminary data, we hypothesize that increasing the number and function of anti- viral TG-resident TEM/TRM CD8+ T cells, by prime/pull immunotherapeutic vaccination combined with PD-1 and CTLA-4 immune checkpoints blockade, should significantly decrease HSV spontaneous reactivation (as measured by shedding in tears).
Our Specific Aims are:
Aim 1 : Test the hypothesis that therapeutic prime/pull vaccination of HSV-1 latently infected HLA Tg rabbits, using human HSV-1 CD8+ TEM/TRM cell epitopes (prime) and neurotropic AAV8 vectors expressing rabbit CXCL9, CXCL10, and CCL5 T-cell-attracting chemokines (pull), will increase the number of TG-resident anti-viral CD8+ TEM/TRM cells and reduce HSV-1 spontaneous reactivation and virus shedding in tears.
Aim 2 : Test the hypothesis that prime/pull therapeutic vaccination, together with blockade of PD-1 and CTLA-4 immune checkpoints will result in even more functional CD8 TEM/TRM cells in the TG, and produce a more robust protection against HSV-1 reactivation and virus shedding in tears. The prime/pull vaccine combined with immune checkpoints blockade is an innovative approach to treat blinding recurrent herpetic disease.

Public Health Relevance

The ultimate objective of the proposed mechanistic and translational research, which uses a unique HLA transgenic rabbit model of HSV-1 spontaneous reactivation, as determined by shedding of reactivated virus in tears, is to understand the interaction between CD8+ T cells and HSV-1. Exploring the fundamental processes of herpes CD8+ T cell immunity should inspire novel vaccines and lead to the design of novel immuno-therapeutic strategies to treat blinding recurrent herpetic disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019896-07
Application #
9245698
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Mckie, George Ann
Project Start
2010-09-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
7
Fiscal Year
2017
Total Cost
$417,148
Indirect Cost
$147,149
Name
University of California Irvine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Esteves, Pedro J; Abrantes, Joana; Baldauf, Hanna-Mari et al. (2018) The wide utility of rabbits as models of human diseases. Exp Mol Med 50:66
Lopes, Patricia P; Todorov, George; Pham, Thanh T et al. (2018) Laser Adjuvant-Assisted Peptide Vaccine Promotes Skin Mobilization of Dendritic Cells and Enhances Protective CD8+ TEM and TRM Cell Responses against Herpesvirus Infection and Disease. J Virol 92:
Khan, Arif A; Srivastava, Ruchi; Vahed, Hawa et al. (2018) Human Asymptomatic Epitope Peptide/CXCL10-Based Prime/Pull Vaccine Induces Herpes Simplex Virus-Specific Gamma Interferon-Positive CD107+ CD8+ T Cells That Infiltrate the Corneas and Trigeminal Ganglia of Humanized HLA Transgenic Rabbits and Protect again J Virol 92:
Srivastava, Ruchi; Hernández-Ruiz, Marcela; Khan, Arif A et al. (2018) CXCL17 Chemokine-Dependent Mobilization of CXCR8+CD8+ Effector Memory and Tissue-Resident Memory T Cells in the Vaginal Mucosa Is Associated with Protection against Genital Herpes. J Immunol 200:2915-2926
Srivastava, Ruchi; Coulon, Pierre-Grégoire; Roy, Soumyabrata et al. (2018) Phenotypic and Functional Signatures of Herpes Simplex Virus-Specific Effector Memory CD73+CD45RAhighCCR7lowCD8+ TEMRA and CD73+CD45RAlowCCR7lowCD8+ TEM Cells Are Associated with Asymptomatic Ocular Herpes. J Immunol 201:2315-2330
Nesburn, Anthony B; BenMohamed, Lbachir (2017) A Tribute to Professor Steven L. Wechsler (1948-2016): The Man and the Scientist. Curr Eye Res 42:161-162
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
Srivastava, Ruchi; Khan, Arif A; Garg, Sumit et al. (2017) Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44high CD62Llow CD8+ TEM Cells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Her J Virol 91:
Srivastava, Ruchi; Khan, Arif A; Chilukuri, Sravya et al. (2017) CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8+ TEM and CD8+ TRM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease. J Virol 91:
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

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