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.
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.
Showing the most recent 10 out of 53 publications
