# Investigating novel host factors promoting human papillomavirus infection

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $38,992

## Abstract

Project Summary/Abstract:
Human papillomavirus (HPV) infects nearly 80 million U.S. adults, and is the primary cause of cervical,
anogenital, and oropharyngeal cancers. Unfortunately, HPV vaccines have been poorly utilized and provide no
therapeutic value for existing infections, leaving much of the population susceptible to HPV-related cancers. To
initiate infection, HPV binds to a series of extracellular receptors and is endocytosed by the host cell. HPV is
then recruited to the host factor γ-secretase in the endosome by an unknown mechanism, enabling it to
act as a chaperone to insert the viral capsid protein L2 across the endosomal membrane. This exposes
L2 to the cytosol, which in turn recruits host factors that direct the virus along an infectious route through the
Golgi apparatus and to the nucleus. Despite HPV’s significant impact on human health, there is limited
understanding of its specific entry pathway through the host cell.
Preliminary data suggest a role for the host p120-catenin (p120) in regulating the early trafficking steps of HPV
along an infectious route. Our research group first identified an HPV-p120 interaction via mass-spectrometry,
and we have since demonstrated that this interaction occurs at early infection time-points. Importantly, p120 is
essential for productive HPV infection. Further experiments suggest that p120 is required for targeting HPV to γ-
secretase for insertion of the viral capsid protein L2 across the endosomal membrane. However, as p120 is a
cytosolic factor, it must be interacting with HPV via a transmembrane protein. Thus, we tested the role of
cadherins – transmembrane cell adhesion molecules known to bind both p120 and γ-secretase – in HPV
infection. Preliminary data show that in addition to binding HPV at early time-points, cadherins are also required
for productive HPV infection. Together, these data suggest the cell-adhesion cadherin molecule, in
conjunction with cytosolic p120, binds to HPV at the cell surface, and promotes endocytosis of the virus
to the endosome. As p120 is known to deliver cadherin to γ-secretase, we further hypothesize that p120
targets the HPV-cadherin complex to endosome-localized γ-secretase so that the virus can reach γ-
secretase for membrane insertion of the viral protein L2. To further test this hypothesis, we will elucidate the
precise mechanism by which the cadherin-p120 complex promotes endocytosis of HPV to the endosome to
initiate HPV infection (Aim 1), and how p120 then targets the virus to γ-secretase for membrane insertion (Aim
2) – a critical step of infection. The combined use of cell-based, biochemical, and infection studies will be
employed to tackle the questions at hand. Insights gained through these studies should illuminate intrinsic
intracellular transport mechanisms. More importantly, identifying the cellular factors mediating HPV infection may
provide new therapeutic strategies to combat HPV infections.

## Key facts

- **NIH application ID:** 10327601
- **Project number:** 5F31AI152365-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Mara Calypso Harwood
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,992
- **Award type:** 5
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10327601

## Citation

> US National Institutes of Health, RePORTER application 10327601, Investigating novel host factors promoting human papillomavirus infection (5F31AI152365-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10327601. Licensed CC0.

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