# Defining Early Stages of Polyomavirus CNS Pathogenesis and Immunity

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2022 · $430,944

## Abstract

ABSTRACT
JC polyomavirus (JCPyV), a ubiquitous human pathogen, causes several devastating brain diseases in
immune compromised individuals. The most notable of these JCPyV-associated CNS diseases is the
frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML). PML, an
AIDS-defining lesion in the pre-cART epoch, has emerged as a life-threatening complication in patients
receiving immunomodulatory agents for autoimmune and inflammatory disorders and treatment for certain
hematological malignancies. Among the rapidly expanding list of PML-associated biologics, natalizumab
(Tysabri®) has the highest incidence and is an ominous sequela for multiple sclerosis (MS) patients who
otherwise benefit from dramatic reductions in relapses using this immunomodulatory agent. Drug withdrawal,
the only therapeutic option for PML, is often complicated by a high-mortality cerebral inflammatory reaction. No
anti-JCPyV agents are available. Lack of a tractable animal model of polyomavirus-induced CNS disease is an
acknowledged bottleneck to elucidating PML pathogenesis, timmunological mechanisms that control JCPyV, in
vivo evaluation of agents that inhibit polyomavirus replication in tissue culture, and uncovering early events that
presage irreversible JCPyV-associated neuropathology – the focus of this renewal application. Using mouse
polyomavirus (MuPyV), we developed a natural virus-host model of polyomavirus-associated CNS disease. In
this renewal application, we will leverage two key findings made under the parent R01 grant: (1) Mapping
JCPyV-PML VP1 capsid protein mutations to MuPyV’s VP1 confers escape from virus-neutralizing antibodies
(nAb) while preserving CNS tropism; and (2) STAT1-dependent innate immunity limits infection of the
ventricular ependyma, a critical barrier to subsequent brain parenchymal infection. Both findings, which parallel
those of JCPyV, lay the foundation for the two key questions raised in this renewal application: (1) Is the
ependyma the staging ground for polyomavirus invasion of the brain parenchyma?; and (2) Does T cell
deficiency open the door for outgrowth of nAb-escape virus variants? The proposed studies will make use of
cutting edge advances in next-generation sequencing to uncover rare VP1 mutations in vivo, custom cryo EM
image reconstruction approaches to define endogenous VP1 nAb epitopes and nAb escape mechanisms, and
high-resolution 3D imaging of mouse brains to visualize viral CNS entry and spread. Findings from these
studies will answer fundamental questions about innate and adaptive immune control of JCPyV and potentially
improve criteria for identifying patients at risk for JCPyV-associated CNS diseases.

## Key facts

- **NIH application ID:** 10365345
- **Project number:** 2R01NS092662-06
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Aron Eliot Lukacher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $430,944
- **Award type:** 2
- **Project period:** 2016-05-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365345

## Citation

> US National Institutes of Health, RePORTER application 10365345, Defining Early Stages of Polyomavirus CNS Pathogenesis and Immunity (2R01NS092662-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10365345. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*