# Mechanisms of varicella virus-induced multisystem disease using a primate model

> **NIH NIH P01** · UNIVERSITY OF COLORADO DENVER · 2020 · $1,019,143

## Abstract

By 2050, the number of Americans 65 years and older is projected to be 83.7 million, and the burden of
diseases and healthcare costs will be staggering. An important cause of multi-system disease in the elderly is
varicella zoster virus (VZV) reactivation. More than 95% of humans harbor latent VZV in their ganglia following
primary infection (varicella, chickenpox) and 50% of them will reactivate VZV by 85 years of age. Serious
complications of VZV reactivation include postherpetic neuralgia (PHN), giant cell arteritis, burning mouth
syndrome, stroke, multi-infarct dementia, blindness, esophagitis, pneumonitis, and gastroparesis. Thus, VZV
reactivation affects multiple organs. VZV-induced persistent inflammation has emerged as an important
pathologic contributor in most of these disorders. The mechanism(s) by which inflammatory cells persist in
infected tissue is unknown; however human vascular cells infected in vitro with VZV show downregulated
expression of programmed death ligand 1 (PD-L1) and major histocompatibility complex 1. Decreased PD-L1
expression contributes to persistent inflammation in autoimmune diseases, raising the possibility that VZV-
induced downregulation of PD-L1 also contributes to persistent inflammation. Since VZV is an exclusively
human virus, we will investigate the role of virus-induced PD-L1 dysregulation across multiple, clinically
relevant tissues in non-human primates infected with simian varicella virus (SVV), a model that we developed
in the last two decades. SVV, the primate counterpart of VZV, causes varicella on primary infection,
establishes latency in ganglia, and reactivates later to produce zoster and multi-system disease. Preliminary
results reveal SVV antigen- and CXCL10-induced T cell infiltration in ganglia 4 months after tacrolimus-
induced SVV reactivation in rhesus macaques, similar to the chronic ganglionitis seen in PHN patients. Like
VZV, SVV infection of rhesus fibroblasts in culture leads to decreased PD-L1 expression. Thus, we
hypothesize that after SVV reactivation, viral antigen and activated immune cells persist in multiple
tissues for months, in part due to dysregulation of PD-L1, thereby contributing to clinical disease seen
in inflamed tissue in the elderly. To test our hypothesis, we will analyze the extent of SVV infection and
associated inflammation in multiple tissues longitudinally after zoster (Aim 1). We will also correlate the
composition, activation state and function of immune cells in multiple tissues longitudinally after zoster with the
presence of SVV and inflammation (Aim 2). Overall, these studies in the non-human primate model of VZV
reactivation will provide insight into multiple virus-infected tissues, not available in humans, to elucidate the
mechanisms of viral persistence and inflammation, information that will be translatable to development of new
intervention strategies to inhibit multi-system disease caused by VZV in elderly humans.

## Key facts

- **NIH application ID:** 9878047
- **Project number:** 5P01AG032958-12
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** RAVI MAHALINGAM
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,019,143
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878047

## Citation

> US National Institutes of Health, RePORTER application 9878047, Mechanisms of varicella virus-induced multisystem disease using a primate model (5P01AG032958-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878047. Licensed CC0.

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