# Manipulation of innate immunity by Polyomavirus T antigens

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $409,377

## Abstract

Project Summary
BKV is a Polyomavirus that infects most of the human population. BKV typically establishes a lifelong,
asymptomatic, persistent infection. Occasionally healthy humans excrete a small number of BKV particles in
urine, and this, coupled with the fact that BKV grows productively in established kidney cell lines, has led to the
view that the virus persists in the urinary tract. While harmless in most cases, BKV can undergo productive
infection and induce an inflammatory response that results in serious diseases, including nephropathy and
hemorrhagic cystitis in immunosuppressed patients. There is little knowledge as to why BKV is tropic for the
kidney and whether its tropism is restricted to the urinary system. Furthermore, the factors governing the
equilibrium between BKV productive infection and persistent infection are unknown.
This application focuses on understanding the basis for cellular responses that lead to productive or persistent
infection. BKV undergoes a productive infection in primary human renal proximal tubule epithelial cells (RPTE),
characterized by extensive cell death and the release of about 40 infectious particles/cell. In contrast, BKV
establishes a low-level persistent infection in vascular endothelial cells (VEC), causing minimal cytopathic
effect with ~10% of the cells expressing viral proteins throughout two months of passaging. RNA-seq shows
that BKV induces many cell cycle genes regulated by the E2F family of transcription factors in both RPTE and
VEC. In addition, many interferon-stimulated genes (ISGs) are upregulated in response to BKV infection of
VEC but not of RPTE.
This research will use human primary human VEC cultures to identify the factors that influence infection
outcomes: productive or persistent. Single cell transcriptomics will be applied to mock and BKV-infected VEC
to assess the response of cell subpopulations to infection and to identify genes that play a role in restricting
BKV replication. The activation of the interferon response by BKV infection in VEC will be assessed using both
molecular and functional (CRISPR knockout) approaches to identify components of the pathway that are
critical for limiting viral infection. Specific viral mutants will be used to determine what viral functions are
required for the induction of the interferon response, as well as at which stage of the viral infection ISGs are
induced. Click chemistry will be used to determine which cellular factors modulate the balance between
productive and persistent infection. A combination of approaches will be used to identify cellular genes that
distinguish restricted versus productively infected cells.
This work will significantly advance our knowledge of BKV pathogenesis by characterizing the viral interaction
with the innate immune system and by identifying cellular factors that promote or restrict BKV infection in a
cell-type specific manner and will provide insights useful for the design of antiviral agents.

## Key facts

- **NIH application ID:** 10030247
- **Project number:** 1R01AI153156-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JAMES M PIPAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,377
- **Award type:** 1
- **Project period:** 2020-06-17 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10030247

## Citation

> US National Institutes of Health, RePORTER application 10030247, Manipulation of innate immunity by Polyomavirus T antigens (1R01AI153156-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10030247. Licensed CC0.

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