John Doorbar (United Kingdom)

University of Cambridge Pathology

Presenter of 4 Presentations

 Conference Calendar
Basic Research / Virus Life Cycle ePoster

HPV PROTEIN FUNCTIONS ARE LINKED TO THE DISTINCT HOMEOSTASIS MECHANISMS THAT REGULATE THEIR EPITHELIAL NICHES (ID 1273)

Session Date
07/21/2020
Session Time
10:00 - 17:00
Room
ePoster
Session Type
Poster Viewing - 20-24 July
Session Name
Basic Research / Virus Life Cycle
Lecture Time
10:01 - 10:02
Presenter
Authors

Abstract

Introduction

The sexually transmitted alpha HPV types infect distinct epithelial niches. We have examined the molecular pathways that regulate normal epithelial homeostasis at four genital target sites, including the vulva, the ectocervix, the cervical transformation zone and the endocervix in order to explain the evolution of high and low risk HPV protein functions, and their mode of HPV persistence.

Methods

Patterns of HPV gene expression in clinical biopsy material, have been correlated by multiplex immunofluoresence imaging with markers of epithelial homeostasis within the femalke genital tract. Molecular pathways were validated using in vitro tissue culture systems that model the epithelial basal layer and the process of reserve cell metaplasia.

Results

Epithelial differentiation controlled by p53 appears a common target of these viruses, which is mediated through the inhibition of p53 transcription, or through E6AP-binding and direct E6-mediated degradation. For high and low risk HPV types, tthis results in an inhibition of Notch-mediated commitment to differentiation, and the persistence of HPV infected cells in the basal layer because of their selective growth advantage. The specific ability of the high-risk HPV types to persist at the cervical transformation zone, requires interference with the molecular pathways that regulate reserve cell proliferation and metaplasia. The balance between Wnt and Notch signalling controls differentiation, quiescence and cell division at this site, with the Hippo pathway controlling cell density. E6 interferes with all three regulatory pthways to ensure persistence, with high risk E6 /PDZ domain protein interactions contributing additionally to disruption of normal cell-cell recognition.

Conclusions

HPV protein functions have evolved to modulatethe homeosatic pathways that regulate their specific epithelial target sites, which for high-risk HPV types includes the reserve cells of the cervical transformation zone. The deregulation of such 'normal ' HPV functions underlies the development of neoplasia. Regulators of HPV-modulated epithelial homeostasis are prime candidates for therapeutic development.

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Workshop 1: HPV Viral Entry, Replication and Trafficking Hall D

Introduction by Chairs (ID 67)

Session Date
07/20/2020
Session Time
09:00 - 10:25
Room
Hall D
Session Type
Basic Science
Session Name
Workshop 1: HPV Viral Entry, Replication and Trafficking
Lecture Time
09:00 - 09:03
Presenter
Authors
IPVC Plenary Session 4 Hall A

Introduction by Chairs (ID 1718)

Session Date
07/24/2020
Session Time
10:30 - 12:05
Room
Hall A
Session Type
Plenary Session
Session Name
IPVC Plenary Session 4
Lecture Time
10:30 - 10:33
Presenter
Authors

Webcast

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Workshop 1: Virus Hall A

How it works? HPV Life Cycle, Entry & Carcinogenesis (ID 40)

Session Date
07/20/2020
Session Time
09:00 - 10:25
Room
Hall A
Session Type
Interdisciplinary
Session Name
Workshop 1: Virus
Lecture Time
09:03 - 09:23
Presenter
Authors

Moderator of 2 Sessions

 Conference Calendar
Basic Science

00030 - Workshop 1: HPV Viral Entry, Replication and Trafficking (ID 5)

Session Type
Basic Science
Session Date
07/20/2020
Session Time
09:00 - 10:25
Room
Hall D
Chair(s)
Plenary Session

01000 - IPVC Plenary Session 4 (ID 52)

Session Type
Plenary Session
Session Date
07/24/2020
Session Time
10:30 - 12:05
Room
Hall A
Chair(s)

Session Webcast