# Antiviral treatment of BK polyomavirus reactivation

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $185,625

## Abstract

Project Summary
 BK polyomavirus (BKPyV) associated nephropathy (PVAN) is the leading cause of kidney transplant
loss (~10%/year). BKPyV infects approximately 80-90% of people during childhood and is kept in check by
the host immune system. However, in transplant patients BKPyV reactivation causes PVAN due to
suppression of their immune system. The current treatment is reduction of immunosuppression, which
increases the risk of graft rejection, but untreated PVAN will result in allograft loss. Patients are routinely
monitored for BKPyV in the urine and the plasma, providing an opportunity to treat early with antivirals,
before decreasing immunosuppression is required. Based on our mechanistic studies, we have identified
two host pathways required for BKPyV production in primary kidney cells that, when inhibited by existing
drugs, reduce viral titers.
 We discovered that bortezomib, a proteasome inhibitor, potently decreases viral titers by 3 logs, at
low doses and without affecting cell fitness. We will also test newer generation proteasome inhibitors that
are less toxic and/or orally available, carfilzomib and ixazomib.
 Given that the proteasome is required early during infection, we sought to inhibit a second host
target that would reduce viral production late in infection, or could potentially eliminate virally infected cells.
BKPyV requires activation of the DNA damage response (DDR) for cell cycle arrest, to prolong S phase for
viral replication and assembly. Inhibiting the DDR activating kinases (ATM and ATR), forces BKPyV
infected, but not mock infected, cells exit S phase, and viral titers are reduced.
 Our studies revealed two potent targets, the proteasome and the DDR, which both have known
inhibitors, one is already FDA approved, and the other is in clinical trials (both are being used for other
indications). The proposed aims will determine the effects of these inhibitors, and combinations of them, on
viral titers, cell viability and cell cycle regulation, using clinical viral isolates to infect primary renal proximal
tubular epithelial cells, which are the natural cell type infected in humans. We will sequence the virus before
and after inhibition studies to determine if there are changes to the viral genome. This proof-of-concept data
is required in order to test the inhibitor(s) in clinical trials (beyond the scope of this study) as antivirals that
can protect against graft loss caused by BKPyV reactivation. There is an urgent need for antivirals that can
either prevent or treat BKPyV reactivation prior to or in conjunction with immunosuppression.

## Key facts

- **NIH application ID:** 10848474
- **Project number:** 5R21AI178734-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Sunnie R Thompson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $185,625
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848474

## Citation

> US National Institutes of Health, RePORTER application 10848474, Antiviral treatment of BK polyomavirus reactivation (5R21AI178734-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10848474. Licensed CC0.

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