Papillomavirus Life Cycle Organization and Biomarker Selection
Disease Markers
0278-0240
Papillomavirus life cycle organization and biomarker selection
John Doorbar 0
0 National Institute for Medical Research , The Ridgeway, Mill Hill, London, NW7 1AA , UK Tel.:
Human papillomaviruses (HPVs) are a diverse group of viruses that cause epithelial lesions of varying severity. Of the 100 or so types that have been identified, around 40 can infect the cervix, with a subset of these causing lesions that can progress to high-grade neoplasia and cervical cancer. These high-risk types are prevalent in the general population, and can predispose to the development of cancer in women who cannot resolve their infection. Virus infection usually leads to the establishment of productive flat warts, or to maintenance of the viral genome in an asymptomatic or latent state. Virus synthesis depends on the ordered expression of viral gene products as the infected basal cell migrates towards the epithelial surface. E7 is expressed in the lower epithelial layers, and is followed eventually by the expression of E4 and L1 closer to the epithelial surface. This ordered pattern changes in characteristic ways during neoplastic progression and latency, and can be irreversibly fixed following integration of the viral genome into the host cell chromosome. Our understanding of expression patterns and their significance, is beginning to explain the nature of disease progression, and offers a rational basis for the selection of biomarkers that may be used to predict disease status and prognostic outcome.
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Human papillomaviruses (HPV) complete their
productive cycle in stratified epithelial tissue such as
cutaneous skin or mucosal epithelium. They can infect
many epithelial sites and cause a wide variety of
epithelial lesions, including common warts, verrucas,
laryngeal papillomas, and genital condyloma. The
different types of epithelial lesion, are in general, caused
by different groups or types of HPV, with some types
showing a very restricted tissue tropism [
6,34
]. This is
the case with viruses such as HPV1, which causes
cutaneous lesions at palmar and plantar surfaces (Fig. 1A).
DNA sequence analysis over the last 25 years has
shown that papillomaviruses are a very diverse group
with over 100 human members [
34
]. Most HPV types
belong to the Alpha or Beta genus, with the two groups
having quite distinct biology and life cycle patterns.
The Alpha papillomaviruses are found only in humans
and primates, and it is this group that contains the HPV
types that are frequently associated with cervical
cancer. HPV16 (α9) causes over 50% of all cervical
cancers, while HPV18 (α7) is responsible for around 20%
of cases (Fig. 1B). These HPV types are classified as
high-risk, and are amongst 20 or so such viruses that
infect the cervix (Fig. 1B). The Alpha papillomaviruses
also contain low-risk members that infect the cervix,
but these are not generally associated with cervical
cancer. HPV types such as HPV6 and HPV11 (α10) are the
best studied of these, and are also responsible for the
production of external genital warts that can be a
problem in young adults. Although not generally life
threatening, such lesions can be difficult to treat effectively
in some patients [
94
]. The Alpha papillomavirus genus
also contains cutaneous HPV types such as HPV2 (α4),
which is a prominent cause of common warts in
children. The different biology of Alpha papillomavirus
members (high-risk, low-risk and cutaneous) is clearly
reflected at the level of virus evolution, when whole
genomic sequences are compared (Fig. 1B).
Beta papillomaviruses are evolutionarily distinct
from the Alpha genus (Fig. 1A), and appear to cause
widespread in-apparent or asymptomatic infections in
the general population, with children becoming
infected at an early age. In immunosuppressed patients,
and in individuals suffering from the inherited disease
Epidermodysplasia Verruciformis (EV), these viruses
can spread unchecked, and have been implicated in
the development of non-melanoma skin cancer
cancer [
55,96
]. EV patients carry mutations in their
EVER1/TMC6 or EVER2/TMC8 genes, which renders
them particularly susceptible to these viruses [
97,112
].
The remaining HPV types come from the Gamma, Mu
and Nu genus, and cause visible cutaneous papillomas
that do not generally progress to cancer (Fig. 1A). Only
two Mu HPV types are known (HPV1 and 63), and the
Nu Genus comprises only one member.
2. Similarities in the organization of all papillomavirus genomes
All papillomaviruses consist of a double stranded
circular genome of around 8kb containing one
coding strand, encapsidated in an icosohedral protein shell
made up of a major (L1) and minor (L2) coat protein
(Fig. 2A). 360 molecules of L1 and approximately 12
molecules of L2 are needed for the formation of an
infectious virion [
76
]. The L1 and L2 proteins are
conserved across widely divergent papillomaviruses, and
along with E1 and E2, are key viral gene products that
are thou (...truncated)