Therapeutic control of HSK by CD80

NIH Pandemic-Era Grants

Pandemic Era Grants

2019

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Principal Investigator: HOMAYON  GHIASI
Organization: CEDARS-SINAI MEDICAL CENTER
Fiscal Year: 2019
Award: $472,500
Funding agency: National Eye Institute

Project Summary
 Following ocular primary herpes simplex virus type-1 (HSV-1) infection, the virus replicates in the eye
and establishes latency in the trigeminal ganglia (TG). In a latently infected individual, the virus can
occasionally reactivate and travel back to the eye causing recurrent disease. This reactivation from latency is
the major cause of corneal scarring (CS) in HSV-1 infection of the eye. We have shown previously that the
elicitation of neutralizing antibody alone can protect immunized mice from eye disease and death; however, it
does not protect the immunized mice from virus replication in the eye and the establishment of latency in the
TG. We therefore focused on the mechanisms by which HSV-1 may subvert the ability of the immune system to
clear the virus, limit viral load, and prevent establishment of latency. We have generated compelling preliminary
data that suggest the novel hypothesis that HSV-1 viral gB suppresses the host CD80 co-stimulatory molecule
and that this leads to reduced CD8+ CTL activity in the eye and TG of ocularly infected mice, which in turn leads
to less effective and delayed clearance of virus and susceptibility to establishment of latency. We will test this
hypothesis and its corollary that provision of exogenous CD80 can reverse the negative effects of gB on ocular
HSV-1 infection. We propose to: (1) Determine whether downregulation of CD80 by HSV-1 gB is responsible
for the absence of a robust effector CD8+ T-cell response in the corneas and TG of ocularly infected mice
during primary infection. This will include analysis of the mechanism by which gB suppresses the transcription
of CD80; (2) Determine whether expression of CD80 by a recombinant HSV-1 (HSV-CD80) will compensate for
the suppressive effects of HSV-1 gB leading to a significant reduction of virus replication in the corneas and TG
of infected mice; and (3) Determine whether binding of expressed CD80 to PD-L1 on DCs will reduce the
binding of PD-L1 to PD-1 on T cells thus leading to reduced T-cell exhaustion and improved virus clearance in
the eye and TG.
CLINICAL SIGNIFICANCE: HSV-1 infections are among the most frequent serious viral eye infections in the
U.S. and are a major cause of viral-induced blindness. The results generated by this study will potentially
establish a previously undescribed mechanism underlying viral immune evasion that could be exploited to
better manage HSV infection. In light of recent failure of a large scale phase III HSV-1 vaccine trial, our
approach may help design a more efficacious vaccine.

Terms: <Adjuvant><Animals><Antibody Response><B7-1><B7-H1><B7H1><BB1><Back><Binding><Blindness><CD25><CD274><CD28LG><CD28LG1><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD80><CD80 gene><CD8B><CD8B1><CD8B1 gene><Cessation of life><Cicatrix><Cornea><DNA><DNA Vaccines><Data><Death><Deoxyribonucleic Acid><Disease><Disorder><Dorsum><Down-Regulation><Downregulation><Exclusion><Eye><Eye Infections><Eye diseases><Eyeball><Failure><Ganglia><Gasser's Ganglion><Gasserian Ganglion><Gene Transcription><General Viruses><Genetic Transcription><Glycoproteins><Goals><HSV><HSV-1><HSV1><Herpes Simplex Keratitis><Herpes Simplex Virus><Herpes Simplex Virus 1><Herpes Simplex Virus Type 1><Herpes labialis Virus><Herpesvirus 1><Herpetic Keratitis><IL2R><IL2RA><IL2RA gene><Immune Evasion><Immune response><Immune system><Immunization><Immunize><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><Individual><Infection><Keratitis><LAB7><LYT3><Lead><Life><Light><Measures><Messenger RNA><Methods><Mice><Mice Mammals><Molecular><Molecular Interaction><Murine><Mus><Naked DNA Vaccines><Neural Ganglion><Ocular Herpes Simplex><Ocular Infections><PD 1><PD-1><PD-L1><PD1><PD1 gene><PDCD1 Ligand 1><PDCD1L1><PDCD1LG1><PDCD1LG1 gene><PDL1><Pb element><Phase><Photoradiation><Predisposition><Prevention><Primary Infection><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Protein Subunits><Publishing><RNA Expression><Receptor Protein><Recombinant DNA Vaccines><Recombinants><Recurrence><Recurrent><Recurrent disease><Relapsed Disease><Role><SLEB2 gene><Scars><Semilunar Ganglion><Simplexvirus><Structure of trigeminal ganglion><Subunit Vaccines><Susceptibility><T cell response><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TCGFR><Testing><Therapeutic><Transcript><Transcription><Travel><Trigeminal Ganglias><Trigeminal Ganglion><Vaccinated><Vaccines><Viral><Viral Burden><Viral Eye Infections><Viral Load><Viral Load result><Viral Ocular Infections><Virus><Virus Replication><Wild Type Mouse><acute infection><allergic/immunologic body system><allergic/immunologic organ system><cicatrix corneal><clinical significance><clinically significant><corneal><corneal scar><design><designing><exhaustion><eye disorder><heavy metal Pb><heavy metal lead><herpes simplex i><host response><immunoresponse><improved><latent infection><mRNA><neutralizing antibody><new approaches><novel><novel approaches><novel strategies><novel strategy><ocular herpes><ophthalmopathy><prevent><preventing><programmed cell death 1><programmed cell death protein 1><programmed death 1><prophylactic><reactivation from latency><receptor><response><sle2><social role><systemic lupus erythematosus susceptibility 2><thymus derived lymphocyte><vaccination study><vaccination trial><vaccine efficacy><vaccine study><vaccine trial><viral multiplication><viral replication><virus multiplication><vision loss><visual loss>