Biology of HPV Mediated Carcinogenesis and Tumor Progression

Abstract

Human papillomavirus (HPV) is a ubiquitous DNA virus that infects squamous epithelia. Though HPV only encodes 8 genes, it is capable of causing cellular transformation and ultimately cancer in host cells. In this article we review the classification of HPV viruses, their genetic structure and life cycle, viral gene biology, and provide an overview of the role of HPV in cancer. We explain how the viral life cycle can lead to integration of viral DNA into the host genome leading to increased cell cycle progression, decreased apoptosis, altered DNA repair, and chromosomal instability. We describe the multifaceted roles of the canonical oncogenes E6 and E7 in promoting tumorigenesis and the important role of other viral genes in regulating cancer development. We also review how the virus actively suppresses innate and adaptive immunity to evade immune detection and promote a pro-tumorigenic microenvironment. The biology presented here will serve as a foundation to the other chapters in this edition and we hope it will incite enthusiasm for continued research on this fascinating virus that causes significant morbidity and mortality worldwide.

Figure 1:

The Human Papillomavirus life cycle and path to transformation and carcinogenesis. (A) HPV gains entry to the mitotically active basal cells in squamous epithelia often through microwounds in the tissue. Following infection of basal cells, HPV initiates its own viral genome replication using the E1, E2, and E4 proteins, while E6 and E7 function to promote host cell proliferation and prevent apoptosis. As the keratinocytes differentiate (upward direction in the figure), L1 and L2 are transcribed in order to package the many copies of newly replicated viral DNA into capsids. Complete virions are then shed from the surface of the squamous epithelium in a non-lytic manner. (B) Though viral replication is HPV’s primary goal, the viral genome can also be amplified and remain episomal (purple circles) in the host cells for long periods of time, though viral E6 and E7 gene expression is kept low in this state. After many rounds of mitosis, the viral genome can become integrated into the host genome (red circles), leading to upregulation of the oncoproteins E6 and E7, increased cell proliferation with relaxed cell cycle checkpoints, and increased chromosomal instability leading to aneuploidy, dysplasia and ultimately carcinoma. Created with BioRender.com

Figure 2:

Diverse functions of high-risk HPV E6 and E7 proteins. Collectively, these functions result in transformation of the host cell, increased cell cycle progression, decreased apoptosis, immune evasion, and chromosomal instability, which can lead to carcinogenesis and tumor formation.