Herpes simplex virus type 1 (HSV-1) is a highly successful neurotropic virus of humans that resides in the nervous system in a latent/persistent state. The morbidity of the virus infection resides with reactivation/re- emergence of the virus from latency/persistence that can result in severe and life-threatening encephalitis with profound chronic neurologic deficits in survivors. Over the past two decades, several labs have reported the generation of vaccines to HSV-1, typically subunit vaccines consisting of one or more viral-encoded glycoprotein. The experimental vaccines have been found to show various degrees of efficacy that primarily focus on sterile immunity and the CD8+ T cell response. We have recently characterized a highly efficacious vaccine, termed HSV-1 0?NLS, against challenge with a lethal dose of HSV-1 and found it to block virus shedding, replication, spread, and establishment of latency in mice challenged with 10x the LD50 of HSV-1 in comparison to naive or gD-2 subunit vaccinated mice. We propose to test the hypothesize that this vaccine generates a highly robust and efficacious immune response primarily via the production of neutralizing antibody that hinders virus infection, replication, and spread following primary infection, and restores the host immune response following therapeutic application. In this application, we will fully evaluate HSV-1 0?NLS against HSV-1 infection relative to local virus replication, spread to the central nervous system (CNS), and innate and adaptive immune responses in the trigeminal ganglion (TG) and CNS following stereotaxic injection of HSV-1 into the TG (aim 1). Furthermore, we will also characterize the role of tripartite motif-containing 21 (TRIM21) in antibody-mediated clearance of virus from infected tissue to test the hypothesis animals vaccinated with 0?NLS possess durable polyclonal antibodies (IgG) that activate the TRIM21 pathway in cells to target virus for degradation (aim 2). The results of this study will validate the pre- clinical application of this vaccine as an authentic candidate to further assess in the human patient.

Public Health Relevance

Herpes simplex virus type 1 (HSV-1) is a prominent human neurotropic viral pathogen with worldwide prevalence of over 3 billion individuals and treatment of new and recurrent cases costing in excess of 2 billion USD annually. We have developed a vaccine that shows significant promise in an experimental animal model. Prevention of viral acquisition and reduction in the incidence of reactivation would save US taxpayers millions annually and reduce the burden and stigma of patients that experience viral reactivation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Beisel, Christopher E
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University of Oklahoma Health Sciences Center
Schools of Medicine
Oklahoma City
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Menendez, Chandra M; Carr, Daniel J J (2017) Herpes simplex virus-1 infects the olfactory bulb shortly following ocular infection and exhibits a long-term inflammatory profile in the form of effector and HSV-1-specific T cells. J Neuroinflammation 14:124
Menendez, Chandra M; Carr, Daniel J J (2017) Defining nervous system susceptibility during acute and latent herpes simplex virus-1 infection. J Neuroimmunol 308:43-49
Zander, Ryan A; Guthmiller, Jenna J; Graham, Amy C et al. (2016) Type I Interferons Induce T Regulatory 1 Responses and Restrict Humoral Immunity during Experimental Malaria. PLoS Pathog 12:e1005945
Royer, Derek J; Conrady, Christopher D; Carr, Daniel J J (2016) Herpesvirus-Associated Lymphadenitis Distorts Fibroblastic Reticular Cell Microarchitecture and Attenuates CD8 T Cell Responses to Neurotropic Infection in Mice Lacking the STING-IFN?/? Defense Pathways. J Immunol 197:2338-52
Menendez, Chandra M; Jinkins, Jeremy K; Carr, Daniel J J (2016) Resident T Cells Are Unable To Control Herpes Simplex Virus-1 Activity in the Brain Ependymal Region during Latency. J Immunol 197:1262-75
Royer, D J; Carr, D J J (2016) A STING-dependent innate-sensing pathway mediates resistance to corneal HSV-1 infection via upregulation of the antiviral effector tetherin. Mucosal Immunol 9:1065-75
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Chucair-Elliott, Ana J; Conrady, Christopher; Zheng, Min et al. (2014) Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells. Glia 62:1418-34
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Bryant-Hudson, Katie; Conrady, Christopher D; Carr, Daniel J J (2013) Type I interferon and lymphangiogenesis in the HSV-1 infected cornea - are they beneficial to the host? Prog Retin Eye Res 36:281-91

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