# Immediate early events of the HPV life cycle

> **NIH NIH R01** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2021 · $331,688

## Abstract

Human papillomaviruses (HPV) replicate in stratified epithelia of the skin and mucosa and require the terminal
differentiation program to complete their lifecycle. HPV access the basal cells of these epithelia through lesions
and establish infection after genome delivery to the nucleus and initial genome amplification. In the basal cell
compartment of productive infections, genome levels are maintained and early viral transcript levels are low.
Early, intermediate and late transcripts as well as genome levels increase when infected cells enter the
terminal differentiation program. The E6 and E7 oncoproteins prevent differentiated cells from exiting the cell
cycle, resulting in the appearance of the benign lesions typically associated with HPV infection (warts,
papillomas) and allowing genome amplification, late gene expression and virus production. However, some
HPV types including HPV16 are associated with malignancies such as cervical carcinoma. HPV-induced
transformation is initiated with the deregulation of oncogene expression in the long-lived, replication-competent
cells of the basal layer. While we do have a very good understanding of E6 and E7 function during
transformation, the lack of appropriate cell culture models have prevented us from studying immediate early
events following infection of basal cells. Most studies of the HPV life cycle depend on keratinocytes-derived
cell lines established from low-grade lesions or after transfection of viral genome into primary keratinocytes
and outgrowth of HPV DNA-containing cell clones. In contrast to basal cells in productive lesions, HPV-
immortalized cell lines express high levels of the E6 and E7 oncoproteins, which is a requirement for
immortalization. The study of such cell lines allowed an understanding of differentiation-induced changes to
viral gene expression, genome amplification and the role early viral proteins play in this process. However,
many questions regarding early events during the establishment of HPV infection as well as early events of
viral transformation remain unanswered.
Based on our intimate studies of attachment, binding and internalization of HPV16 virions by keratinocytes and
our capability to generate virions using heterologous expression systems, we have now established an
infection model that allows efficient infection of primary human foreskin keratinocytes (HFK) with HPV16
quasivirions. The model mimics natural infection in that (i) it utilizes prebinding of virions to extracellular matrix,
the basement membrane-equivalent; (ii) allows efficient delivery of viral genome to PML nuclear bodies, (iii)
only the early but not the late promoter is active in undifferentiated HFK; (iv) early and late promoter are
responsive to differentiation triggered by growth in methylcellulose or organotypic raft cultures resulting in high
levels of late transcripts; (v) viral genome remains episomal and is amplified upon differentiation; (vi) and
capsid proteins are expressed in...

## Key facts

- **NIH application ID:** 10163808
- **Project number:** 5R01CA211576-05
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Martin Sapp
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $331,688
- **Award type:** 5
- **Project period:** 2017-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163808

## Citation

> US National Institutes of Health, RePORTER application 10163808, Immediate early events of the HPV life cycle (5R01CA211576-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10163808. Licensed CC0.

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