Herpes Simplex Virus type 1 (HSV) infections are ubiquitous in man with >85% of the global adult population being latently infected. HSV encephalitis (HSE) is the most prevalent sporadic viral encephalitis resulting from primary infections in neonates or reactivated latent infections in adults. Although, significant advances i diagnosis of HSE and development of potent antiviral drugs have significantly reduced mortality, most survivors (>60%) suffer severe neurological complications that preclude them returning to independent living;prospects for children who develop cognitive and learning disabilities are particularly bleak. Anatomically and functionally long-term damage from HSE is usually confined to the limbic system in man. Intranasal inoculation of mice seeds infection in this same limbic brain region that supports a variety of functions including memory, emotion, behavior and olfaction. Importantly, inflammatory lesions and prolonged inflammation in the limbic region has been correlated with memory impairment in untreated mice surviving HSV infection. Thus this mouse model is ideally suited for exploring treatments that could ameliorate long-term neurological deficits afflicting most patients surviving HSE. We have shown definitively that the pathology underlying HSE results from exaggerated CNS inflammatory responses rather than virus-induced cytopathology. In contrast to the antiviral drug acyclovir, that blocks only HSV replication, intravenous immunoglobulins (IVIG) exert potent anti-inflammatory and antiviral effects to prevent HSE. We propose neurobehavioral testing of mice surviving HSV brain infection to validate the hypothesis in Specific Aim 1 that combinatorial antiviral-immunotherapy (ACV+IVIG), compared ACV monotherapy, will reduce CNS immunopathology and thereby result in improved neurological outcomes for HSV infected mice.
In Specific Aim 2, the goal is to use serum proteomic profiles to identify protein signatures that are correlated with beneficial anti-inflammatory responses compared to deleterious proinflammatory responses in infected mice receiving combinatorial ACV-IVIG or ACV monotherapy, respectively. Bioinformatic, statistical and Ingenuity Pathway Analysis (IPA) will be used to identify proteins upregulated in IVIG treated mice that converge on pathway(s) implicated in anti-inflammatory responses and thus represent candidate biomarkers. After further testing and validation these biomarkers would be clinically useful for predicting desirable anti-inflammatory, as compared to undesirable proinflammatory responses in patients treated with an antiviral-immunotherapy cocktail incorporating IVIG as an anti-inflammatory and immunomodulatory drug.

Public Health Relevance

Recent clinical and experimental data convincingly implicate exaggerated inflammatory responses in the brain as causing HSV encephalitis (HSE) and the pathology underlying neurological impairment in survivors. We propose neurobehavioral testing of infected mice treated with the antiviral Acyclovir (ACV) alone or ACV+IVIG to validate the hypothesis that combined therapy incorporating IVIG (intravenous immunoglobulins), an anti- inflammatory drug we showed protects against HSE, will also diminish neurological complications in HSE survivors. A second goal is screen the serum of drug treated infected mice for biomolecules that could serve as biomarkers predictive of beneficial anti-inflammatory responses to therapy incorporating IVIG an anti- inflammatory drug.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS085501-01A1
Application #
8771312
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2014-05-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$253,750
Indirect Cost
$103,750
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010