Please
note: You will need Macromedia Flash Player to view this animation. If
you do not have it, you can download it for free from the Macromedia website:
Controls
Green button
= Start
Red Button
= Stop
Blue button
= Resume
(There are several pauses built-in
to the animation. Press blue
to resume play when the animation pauses)
Orange
= Return animation to beginning (appears at the end)
The figure on the left shows a cross-section of the
skin, while the circular diagram on the right shows the HPV 16 genome
(a high-risk type of HPV) and which genes are activated at each stage
in the life cycle.
HPV life cycle
This is intended to accompany the above animation - for a more
detailed account of the HPV life cycle see below or click here
HPV infects basal epithelial cells via microtrauma in
the skin. It uncoats and its DNA enters the nucleus. E6 and E7, the
major transforming genes, are expressed, causing an increase in cell
division. The cells divide and differentiate, carrying the HPV DNA with
them.
As the infected cells differentiated, the E1, 2, 4 and
5 genes are expressed. E1 and 2 are involved in replication of the viral
genome, E4 encodes a protein required for the final stage of replication,
and E5 encodes another transforming protein.
Once the infected cells reach terminal differentiation
the late genes L1 and L2 are expressed, these code for the viral capsid
proteins. The new virus particles are shed with the dead skin cells.
The virus infects the basal layer of the epithelium via minor
abrasions in the skin. It enters the cell, uncoats and delivers its DNA
to the cell's nucleus. The first genes to be expressed are E6 and E7.
These are involved in cell transformation and are responsible for causing
precancerous changes in the host cells by suppressing regulation of the
cell cycle and inhibiting apoptosis, the usual cellular response to excessive
DNA damage.
E6 binds to and inhibits p53, which is active in repressing
the cell cycle in the event of DNA damage, and also in triggering apoptosis
if the damage is too severe to be repaired by the cell. E6 also activates
cellular telomerase, the enzyme that synthesises the telomere repeat
sequences in eukaryotic chromosomes, and this allows the cells to replicate
continuously.
E7 promotes cell division by binding to Rb, a tumour suppressor
protein that usually binds to and inactivates a transcription factor
E2F. E2F unbound from Rb causes transcription of genes involved in DNA
replication and cell division.
The infected basal cells divide and their progeny take
HPV DNA with them. During the early phases of infection the copy number
of the viral genome is between 50 and 100, and the viral genome exists
as extrachromosomal plasmid that replicates as the host cell chromosomes
replicate.
As the infected cells differentiate, the remainder of
the early genes become switched on. E1 and E2 are DNA binding proteins
that regulate transcription and replication of the viral genome - E1
is a helicase and E2 is a transcription factor. For more information
on E2 protein see our Research section. E4
is thought to be involved in activating the productive phase of the
HPV life cycle. E5 is another viral protein involved in transformation,
enhancing the activity of epidermal growth factor (EGF).
As the cells approach terminal differentiation the late
genes, L1 and L2, are activated - they encode the major and minor viral
capsid proteins (respectively). By this point the viral copy number
has been drastically increased so that thousands of virus particles
are produced per cell. As these cells approach the surface of the skin
they are sloughed off, and the virus particles are released to infect
other cells and spread to other hosts.
This web site was created using Microsoft Frontpage by Chris Walmsley (with
thanks to Teresa Gornall)
For problems or questions concerning this website please contact [Teresa
Gornall].
Last updated: September 28, 2005.
