# Mechanisms of Interferon Regulatory Factor Dysfunction by Cutaneous Papillomaviruses

> **NIH NIH K01** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2021 · $129,330

## Abstract

Project Summary/ Abstract
 Papillomavirus (PV) infections significantly impact human health. Mucosal PVs cause virtually all cases
of human cervical cancer, while cutaneous PVs cause severe skin infections and non-melanoma skin cancers
in patients with immunodeficiencies resulting from e.g. HIV infection, organ transplants, or genetic disorders.
Treatments for cutaneous PVs are limited and often ineffective. Thus, there is a critical need for development
of novel therapeutics directed at keratinocytes, the target cell of PV infections. Keratinocytes have the potential
to mount an antiviral response. Viral infection activates interferon regulator factors (IRFs), which upregulate
interferons (IFN) and IFN-stimulated antiviral genes. IRFs and IFNs are also tumor-suppressing, making them
particularly attractive as therapeutic targets for PV infections. However, both mucosal and cutaneous PVs can
repress IRF function and IFN expression. This repression is mediated by the E6 and E7 oncogenes of mucosal
PVs. While limited studies suggest that mucosal and cutaneous PVs differ in their E6 and E7 functions and that
IRF regulation of the IFN response in keratinocytes differs from that in other cell types, there are many more
questions than answers. Like humans, cutaneous PV infections occur in dogs and are more prevalent in
immunodeficient animals. Thus, the dog offers a natural spontaneous animal model for investigation of
cutaneous PV infections and for testing novel therapeutics. Indeed, our preliminary data demonstrate that
canine cutaneous PV E6 and E7 differentially disrupt IFN and IFN-stimulated gene expression in canine
keratinocytes. The long-range goal of our work is to develop novel therapeutics targeting IRFs and the IFN
response for treatment of cutaneous PV infections in immunodeficient patients, using a canine model of PV
infection. We hypothesize here that E6 and E7 from cutaneous PVs enhance viral infection by inhibiting IRF
function in keratinocytes using mechanisms unique to cutaneous PVs. In Aim 1, we will inhibit expression of
IRFs to determine their impact on cutaneous PV infection and on constitutive and inducible expression of IFNs
and IFN-stimulated genes in keratinocytes. In Aims 2 and 3, we will determine the mechanisms for cutaneous
PV E6- and E7-mediated disruption of IFNs and IFN-stimulated gene expression in keratinocytes. Specifically,
we will use mass spectrometry to identify E6 and E7 binding partners that modulate IRF expression and/or
function, and then identify mechanisms for E6 and E7 effects on these binding partners. Using human PV and
keratinocytes will address the human disease; using canine PV and keratinocytes will advance the dog model.
Results will lay the foundation for development of novel therapeutics that would by-pass E6 and E7 deleterious
effects. The mentoring team includes faculty with extensive expertise in keratinocyte biology, IRF and IFN
biology in differentiated cells, PV biology, and mass spectrome...

## Key facts

- **NIH application ID:** 10217281
- **Project number:** 5K01OD023219-05
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** JENNIFER A LUFF
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $129,330
- **Award type:** 5
- **Project period:** 2017-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217281

## Citation

> US National Institutes of Health, RePORTER application 10217281, Mechanisms of Interferon Regulatory Factor Dysfunction by Cutaneous Papillomaviruses (5K01OD023219-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10217281. Licensed CC0.

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