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Principal Investigator: Lbachir BenMohamed
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $409,999
Funding agency: National Eye Institute
SUMMARY/ABSTRACT
Herpes simplex type virus-1 (HSV-1) infects over 3.72 billion people worldwide, including 200 million individuals
in the United States. Following primary infection of the cornea, HSV-1 establishes latency in sensory neurons of
the trigeminal ganglia (TG). Reactivation of HSV-1 from latently infected TG leads to shedding of the virus in
tears causing recurrent ocular herpetic disease, a major cause of infectious blindness in the Western world.
Currenly, an FDA-approved herpes simplex vaccine is unavailable. Our long-term goal is to develop an
immunotherapeutic ocular herpes vaccine. While a role for CD8+ T cells (but not CD4+ T cells) in reducing HSV-
1 reactivations from latently infected TG is gaining wider acceptance, the small numbers of functional tissue-
resident memory CD8+ TRM cells that are present in latently infected TG are not enough to prevent virus
reactivation. We have made several significant findings, during the last funding period: (1) HSV-specific CD8+ T
cells from “naturally protected” HLA-A*0201-positive asymptomatic individuals (who never develop recurrent
ocular herpetic disease despite being infected) mainly targeted five HSV-1 epitopes; (2) Phenotypic and
transcriptomicprofiling indicates that frequent HSV-specific CD8+ TRM cells, which expressed high levels of
tissue-homing and tissue-residency receptors (i.e. CXCR3, IL-2R/IL-15R, CD69, and CD103), found in the TG
of HSV-1 infected HLA-A*0201 transgenic rabbits (HLA Tg rabbits) are associated with decreased virus
shedding; (3) Topical ocular delivery to latently infected HLA Tg rabbits of prototype neurotropic adeno-
associated virus (AAV8) constructs, which express either the T cell attracting CXCL11 chemokine (CXCR3
ligand) or IL-2/IL-15 cytokines (IL-2Rb/IL-15Rb ligands), increased the frequency of TG-resident CD8+ TRM cells
specific to the five immunodominant epitopes; (4) Increased numbers of exhausted TG-resident CD8+ TRM cells
were associated with increased virus shedding in HLA Tg rabbits; and (5) Ex vivo blockade of T cells exhaustion
pathways PD-1, LAG-3 and TIGIT, ex vivo, in rabbit TG explants significantly reduced virus reactivation. Building
on the above published and preliminary results, the central hypothesis of this revised competitive renewal
proposal is that a TG-targeted vaccine that boosts the number, function and longevity of anti-viral TG-resident
CD8+TRM cells will reduce virus reactivation and shedding. Specific Aims: Aim 1: Test the hypothesis that a
tissue-targeted Prime/Pull/Keep therapeutic vaccine (designated as PPK vaccine) that incorporates the five
immunodominant HSV-1 CD8+ TRM cell epitopes (prime), CXCL11 (pull) and IL-2/IL-15 (keep) will boost the
number and longevity of TG-resident CD8+ TRM cells and significantly decrease HSV-1 reactivation in latently
infected HLA Tg rabbits. Aim 2: Test the hypothesis that tissue-targeted PPK vaccine combined with blockade
of PD-1, LAG-3 and/or TIGIT immune checkpoints will increase the number of functional CD8+ TRM cells in the
TG and produce even more robust protection in latently infected HLA Tg rabbits. This translational research is
expected to pave the way towards developing a PPK vaccine to protect against recurrent ocular herpes in man.
Terms: <AAV vector><AAV-based vector><Adeno-Associated Viruses><Afferent Neurons><Antigenic Determinants><Associated Viruses><Binding Determinants><Blindness><Body Tissues><CD183><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CKR-L2><CMKAR3><CXCL11><CXCL11 gene><CXCR3><CXCR3 gene><Cell Body><Cells><Chemokine (C-X-C Motif) Receptor 3><Chemotactic Cytokines><Clinical Treatment Moab><Co-Stimulator><Combination Vaccines><Combined Vaccines><Cornea><Costimulator><Data><Dependoparvovirus><Dependovirus><Domestic Rabbit><Engineering><Epidermal Thymocyte Activating Factor><Epitopes><Eye Drops><Eye Infections><Eyedrops><FDA approved><Frequencies><Funding><G Protein-Coupled Receptor 9><GPR9><Gasser's Ganglion><Gasserian Ganglion><Goals><Grant><H174><HLA A*0201 antigen><HLA-A*0201><HSV><HSV-1><HSV1><Herpes Simplex><Herpes Simplex Infections><Herpes Simplex Keratitis><Herpes Simplex Type 1><Herpes Simplex Virus><Herpes Simplex Virus 1><Herpes Simplex Virus Type 1><Herpes infection><Herpes labialis Virus><Herpes simplex disease><Herpesviridae Infections><Herpesviridae disease><Herpesvirus 1><Herpesvirus Infections><Herpesvirus hominis disease><Herpetic Keratitis><Homing><Homologous Chemotactic Cytokines><I-TAC><IL-15><IL-15 binding protein><IL-15 receptor><IL-15R><IL-2><IL15><IL15 Protein><IL2 Protein><IP-9><IP10><IP10 Receptor><IP10-Mig receptor><IP10-R><IP9><Immunization><Immunodominant Antigenic Determinants><Immunodominant Determinants><Immunodominant Domains><Immunodominant Epitopes><Immunodominant Regions><Immunodominant Sites><Immunotherapeutic agent><Individual><Infection><Intercrines><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-15><Interleukin-15 Precursor><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intramuscular><Intravenous><Investigators><Knowledge><LYT3><Lead><Length of Life><Ligands><Longevity><Lymphocyte Mitogenic Factor><MGC9721><Maps><Memory><Mig Receptor><Mig-R><MigR><Mitogenic Factor><Modeling><Monoclonal Antibodies><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Ocular Herpes Simplex><Ocular Herpetic Disease><Ocular Infections><Oryctolagus cuniculus><PD 1><PD-1><PD-1 blockade><PD-1 checkpoint pathway><PD-1 pathway><PD-1 signaling pathway><PD1><PD1 blockade><PD1 checkpoint pathway><PD1 pathway><PD1 signaling pathway><Pathway interactions><Patients><Pb element><Persons><Phenotype><Position><Positioning Attribute><Primary Infection><Publishing><RNA vaccine><RNA-based vaccine><Rabbits><Rabbits Mammals><Receptor Protein><Recurrence><Recurrent><Research><Research Personnel><Researchers><Residencies><Role><SCYB11><SCYB9B><SIS cytokines><Satellite Viruses><Semilunar Ganglion><Sensory Neurons><Simplexvirus><Structure of trigeminal ganglion><T cell growth factor><T-Cell Epitopes><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Thymocyte Stimulating Factor><Tissues><Topical Drug Administration><Topical application><Transgenic Organisms><Translational Research><Translational Science><Trigeminal Ganglias><Trigeminal Ganglion><United States><Vaccine Design><Vaccine Production><Vaccines><Viral><Viral Shedding><Virus><Virus Shedding><Western World><Work><adeno associated virus group><adeno-associated viral vector><adeno-associated virus vector><administer topically><anti programmed cell death protein 1 checkpoint pathway><anti programmed cell death protein 1 pathway><anti programmed cell death protein 1 signaling pathway><anti-PD-1 blockade><anti-PD1 blockade><apply topically><b-R1><booster dose><booster shot><booster vaccine><check point blockade><checkpoint blockade><chemoattractant cytokine><chemokine><corneal><corneal herpetic disease><cytokine><deliver topically><exhaust><exhaustion><genome scale><genome-wide><genomewide><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><herpes simplex i><herpes simplex virus 1 infection><herpes simplex virus infection><herpes simplex virus keratitis><herpes simplex-1><hsv keratitis><immune check point><immune check point blockade><immune checkpoint><immune checkpoint blockade><immune drugs><immune-based therapeutics><immunecheckpoint><immunologic therapeutics><immunotherapeutics><immunotherapy agent><innovate><innovation><innovative><interleukin-15 receptor><latency/reactivation><mAbs><mRNA vaccine><mRNA-based vaccine><man><monoclonal Abs><multidisciplinary><neuronal><neurotropic><ocular herpes><pathway><prevent><preventing><produce vaccines><programmed cell death 1><programmed cell death protein 1><programmed death 1><promoter><promotor><prototype><reactivation from latency><receptor><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><social role><systemic lupus erythematosus susceptibility 2><therapeutic vaccine><therapeutically effective><thymus derived lymphocyte><topical administration><topical delivery><topical drug application><topical treatment><topically administered><topically applied><topically delivered><topically treated><transcriptome><transgenic><translation research><translational investigation><treat topically><treatment vaccines><vaccine boost><vaccine candidate><vaccine for the treatment><vaccine for treatment><vector><vector-based vaccine><vision loss><visual loss>