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Oncogenic human papillomaviruses

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Abstract and Figures

Human papillomaviruses (HPVs) are an ancient group of viruses with small, double-stranded DNA circular genomes. They are species-specific and have a strict tropism for mucosal and cutaneous stratified squamous epithelial surfaces of the host. A subset of these viruses has been demonstrated to be the causative agent of several human cancers. Here, we review the biology, natural history, evolution and cancer association of the oncogenic HPVs. This article is part of the themed issue ‘Human oncogenic viruses’.
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rstb.royalsocietypublishing.org
Review
Cite this article: McBride AA. 2017 Oncogenic
human papillomaviruses. Phil. Trans. R. Soc. B
372: 20160273.
http://dx.doi.org/10.1098/rstb.2016.0273
Accepted: 9 June 2017
One contribution of 14 to a theme issue
‘Human oncogenic viruses’.
Subject Areas:
cellular biology, evolution, genomics, health
and disease and epidemiology, microbiology,
molecular biology
Keywords:
HPV, papillomavirus, cancer, keratinocyte
Author for correspondence:
Alison A. McBride
e-mail: amcbride@nih.gov
Oncogenic human papillomaviruses
Alison A. McBride
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD 20892, USA
AAM, 0000-0001-5607-5157
Human papillomaviruses (HPVs) are an ancient group of viruses with small,
double-stranded DNA circular genomes. Theyare species-specific and have a
strict tropism for mucosal and cutaneous stratified squamous epithelial sur-
faces of the host. A subset of these viruses has been demonstrated to be the
causative agent of several human cancers. Here, we review the biology, natural
history, evolution and cancer association of the oncogenic HPVs.
This article is part of the themed issue ‘Human oncogenic viruses’.
1. Viral life cycle
(a) Human papillomavirus genome organization
The family Papillomaviridae is a group of small, non-enveloped viruses with
double-stranded DNA circular genomes that are mostly 7– 8 kbp. All papillo-
maviruses encode four conserved core proteins: E1 and E2 are replication
factors [1,2]; and L1 and L2 are capsid proteins [3,4]. In addition, the oncogenic
HPVs encode accessory proteins: E4, E5, E6 and E7 [5– 9]. These proteins modu-
late the cellular environment to make it more conducive for viral replication,
and are important for immune evasion. The genome can be divided into
three regions: the upstream regulatory region (URR) contains cis elements
that control transcription and replication; the early region encodes the E1, E2,
E4, E5, E6 and E7 proteins; and the late region encodes the L1 and L2 structural
proteins. A typical alpha-HPV genome is shown in figure 1. The small genome
is densely packed with overlapping open reading frames and cis regulatory
elements. Transcription occurs in three waves, which are dependent on the
differentiation status of the host cell [10]. Early transcription is initiated from
early promoters situated just upstream from the early coding region and termi-
nated at the early polyadenylation site. Intermediate transcription originates
from the late promoter, and transcribes high levels of the E1 and E2 replication
proteins, but still terminates at the early promoter. Late transcription uses both
the late promoter and late polyadenylation site, and results in high-level
expression of the L1 and L2 proteins.
(b) Overview of human papillomavirus infectious cycle
HPVs infect cutaneous and mucosal sites and take advantage of the highly
organized process of tissue renewal in stratified squamous epithelia. The
virus infects the cells in the lower, basal layer of the epithelium through a
micro-abrasion [11] and establishes a long-term, persistent infection within
these cells. When these infected cells differentiate and move up towards the sur-
face of the epithelium, high-level viral replication and gene expression is
induced. Virions are assembled in the superficial layers and are released from
the epithelium in viral-laden squames ( figure 2). This strategy of infecting
self-renewing cells ensures long-term viral persistence, while restricting high
levels of viral proteins to more differentiated layers of the lesion is thought to
help the virus escape detection by the immune system.
The HPV virion is an icosahedral capsid assembled from 360 molecules of
the L1 protein [4]. The viral genome is packaged into the L1 capsid as a
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mini-chromosome assembled with host histones [12], and up
to 72 copies of the L2 minor capsid protein [13]. HPVs are
thought to access the basal cells through a fissure in the epi-
thelium that exposes the basement membrane [11]. This tactic
allows access to self-renewing cells and promotes cellular
proliferation as part of the wound-healing process, which
could aid in the establishment of the viral infection. The
viral capsid initially interacts with heparin sulfate proteogly-
cans on the basement membrane, which induces a
conformational change that allows the virus to bind to a (as
yet unidentified) secondary receptor on the surface of the
basal keratinocytes [14].
The virion is taken into the cell by endocytosis and is traf-
ficked through the endosomal pathways to the trans-Golgi
network. The virus is uncoated during trafficking and only
the viral mini-chromosome, in complex with L2, enters the
nucleus encased in a membrane vesicle [15]. The cell must
undergo mitosis and nuclear envelope breakdown to allow
the L2-genome complex to access the nucleus [16,17]. Similar
to many other viruses, the L2-genome complex is next
observed adjacent to ND10 nuclear bodies [18]. These
bodies are thought to be important for intrinsic immune
defence, but somewhat counterintuitively, they also are
attractive locations for viruses to establish their replication
and transcription programme [19]. Viruses often reorganize
the components of the ND10 bodies, and likewise the HPV
L2 protein displaces the Sp100 protein, and recruits Daxx
[20], to induce a local environment suitable for initiation of
viral transcription and replication.
Early viral transcripts encode the E1 and E2 replication
proteins to support limited viral DNA amplification [21].
There are three phases of replication in the viral life cycle:
first there is limited DNA amplification when the virus first
infects the cell; next there is maintenance replication, when
the viral genome replicates at a constant copy number in
the proliferating cells of a lesion; and finally there is
L2
E6
L1
E7
E
1
E2
E4
E5
URR
oncogenic
alpha-HPV
protein
function review
reference
E1
origin binding helicase [1]
E2
DNA binding protein; E1 helicase loader; tethers viral genomes to host
chromosomes; transcriptional regulator
[2]
E8^E2
DNA binding repressor protein that limits productive replication [2]
E1^E4 or E4
late protein; reorganizes the dense network of keratins in differentiated cells to
facilitate viral transmission
[5]
L1
major capsid protein, 360 per virion [4]
L2
minor capsid protein, escorts genome through the endocytic pathways into the
nucleus; packages the viral DNA in the capsid
[3]
E6
immune evasion; degrades p53 and PDZ binding proteins; upregulates
telomerase
[7]
E7
immune evasion; degrades pRb family members; epigenetic modulator [8]
E5
only encoded by alpha-HPVs; promotes cell growth; immune evasion [6]
PE
PL
pAE
pAL
ori
Figure 1. Viral genome. Map of an alpha-HPV genome. The URR (upstream regulatory region) contains the replication origin (ori). The early promoter (PE), late
promoter (PL) and early and late polyadenylation sites (pAE and pAL) are indicated.
normal HPV infection CIN1 CIN2 CIN3
cervical intraepithelial neoplasia
invasive cancer
uninfected
extrachromosomal viral DNA, late gene expression
integrated viral DNA, overexpression of E6/E7
Figure 2. Oncogenic progression of cervical infection. Diagram of steps in progression from HPV infection to invasive cervical cancer.
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differentiation-dependent amplification when the viral DNA
is replicated to high copy number to generate progeny virions
[22]. E2 recruits and loads the E1 helicase onto the viral repli-
cation origin, but otherwise the virus relies on cellular
proteins to synthesize viral DNA [22]. Both early and late
amplification of viral DNA engages the cellular DNA
damage response (DDR) [23,24] to support DNA synthesis.
During the maintenance phase of replication, the E2 protein
ensures that the low copy number viral genomes are efficiently
partitioned to the daughter cells by tethering them to host
chromatin [22]. To achieve this, E2 contains both a DNA bind-
ing domain that interacts with conserved sites (E2BS) in the
viral genome, and a ‘transactivation’ domain that interacts
with host chromatin [2]. Notably, this tethering mechanism
is shared by other oncogenic viruses with extrachromosomal
genomes, and is critical for persistent infection [22]. E2 is
also the primary transcriptional regulator of the virus [2].
There are four highly conserved E2BS in the URR regulatory
region of the oncogenic alpha-HPVs that are required for
both replication and transcription functions of E2. E2 either
activates or, more often, represses viral transcription [2]. All
HPVs also encode an E2-derived protein E8^E2 that represses
viral transcription and replication, thus restricting the viral life
cycle and maintaining a low-level persistent infection [2].
E6 and E7 are the oncoproteins of the high-risk alpha-
HPVs. These proteins are less well conserved, and more
specialized than the core proteins of the virus. Through a
multitude of interactions with cellular proteins, they both
promote cellular proliferation and inactivate cell-cycle check-
points to promote viral replication in differentiated cells [7,8].
E7 causes replication stress and epigenetically reprogrammes
cellular circuits that result in oncogene-induced senescence
[25], and there is evidence that viral-mediated inactivation
of the pRb pathway is primarily to counteract this response
[26]. E6 and E7 also disrupt interferon and NFkB signalling
pathways, allowing the virus to persist and escape detection
[27]. There is substantial overlap between immune signalling
and tumour suppression pathways, leading to a hypothesis
that persistent oncogenic viruses target these pathways pri-
marily to escape immune detection, with the unfortunate
side effect of oncogenic promotion [28]. The E5 protein can
facilitate immune evasion by downregulating surface
expression of proteins involved in antigen presentation, and
can also promote proliferation by enhancing EGFR signalling
pathways [6].
In the upper layers of an infected lesion, viral DNA is
amplified to a high copy number. This phase requires induc-
tion of the DDR, which is thought to recruit repair factors that
the virus can hijack to replicate its DNA [23,29]. The E4
protein is also expressed abundantly in the upper layers of
the lesion, where it reorganizes the network of keratin fila-
ments to facilitate virus release and transmission [5]. High
levels of L1 and L2 result in the self-assembly of capsids
that encapsidate viral DNA. Superficial cells containing
arrays of virions are naturally sloughed from the surface of
the epithelium.
2. Evolution of human papillomaviruses
(a) Diversity and rate of evolution
To date, the family Papillomaviridae contains 49 genera and
over 300 individual human and animal papillomavirus
types (http://pave.niaid.nih.gov/). Over 200 types are
HPVs, which are organized into five phylogenetic genera
named alpha, beta, gamma, mu and nu, shown in figure 3
[30]. Papillomaviruses evolve extremely slowly with a
mutation rate only five times that of the host species [31];
this rate is balanced by the relatively rapid generation times
of papillomaviruses versus the highly constrained nature of
the viral genome. Moreover, while HPVs use host DNA poly-
merases to replicate their genomes, this might entail
polymerases specialized for DNA repair [29].
(b) Host range and niche adaptation
Until recently, it was thought that papillomavirus infection
was restricted to Amniotes (mammals, birds and reptiles),
indicating that virus and host had been coevolving for over
300 Myr [32]. However, the recent isolation of a fish (Actinop-
terygii) papillomavirus extends this timeline back for an
additional 120 Myr [33]. The five genera of human papillo-
maviruses are dispersed through the phylogenetic tree,
which indicates that these lineages diverged prior to specia-
tion of the host Homo sapiens [32]. Current thinking is that
papillomaviruses originally diverged to take advantage of
emerging ecological niches in the wide-ranging epidermises
and epidermal appendages of vertebrates. Subsequently,
viruses within each genus continued to coevolve and adapt
to a specific niche of their host [31,32]. It is this final cospecia-
tion and niche adaptation, often tropic to vulnerable cells,
which likely gave rise to the oncogenic HPVs.
(c) Taxonomy of oncogenic human papillomaviruses
The host specificity and benign nature of most papilloma-
virus infections is indicative of a long virus– host
association [32]. Although the majority of animal papilloma-
viruses have been isolated from clinically apparent lesions,
the much greater sampling depth of human epithelia reveals
that most papillomaviruses give rise to subclinical or asymp-
tomatic infections. Out of the five genera of HPVs, four (beta,
gamma, mu and nu) contain only viruses that infect
cutaneous epithelia. The fifth, the alpha genus, is unique in
that it contains HPVs tropic to both cutaneous and mucosal
epithelia. The oncogenic HPVs are a subset of the mucosotro-
pic alpha-HPVs. The 12 ‘high-risk’ oncogenic HPVs are
shown in red in figure 3, and the possibly/probably onco-
genic HPVs are shown in orange. Figure 4ashows the
different human cancers associated with HPV infection, and
figure 4bshows the distribution of oncogenic HPV types
found associated with different cancer sites [35].
(d) Variant human papillomaviruses
Individual HPV types have less than 90% nucleotide
sequence identity in the L1 gene compared with any other
named HPV type [36]. However, variant lineages have
between 1 and 10% differences in the L1 region [37]. Remark-
ably, although HPV evolution is very slow, genetic drift of
HPVs can be used to monitor the migration of ancient
human populations, and indicates that variant diversity
within an HPV type has been evolving for over 200 000
years [38]. Many studies have attempted to identify onco-
genic HPV variants with the highest propensity to cause
cancer; but viral-mediated oncogenesis is a multifaceted pro-
cess with contributions from viral oncogene properties, viral
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persistence and host immunity. It is crucial to have a consist-
ent method to number genomes, and classify variants [37], so
that the huge datasets obtained from next-generation sequen-
cing techniques and epidemiological data can be reliably
compared and used to identify subtle correlations that
might provide important insight into the multifactorial
process of viral-mediated oncogenesis.
3. Human papillomavirus-associated cancers
(a) Alpha human papillomaviruses
Over 15% of human cancers can be attributed to infectious
agents, and almost one-third of these are due to infection
by HPVs [39]. HPVs are highly associated with the develop-
ment of cervical cancer, as well as vaginal, vulvar, anal,
rectal, penile and oropharyngeal cancers [34,40]. In the 2012
the International Agency for Research on Cancer (IARC)
Monographs on the Evaluation of Carcinogenic Risks to
Humans, 12 HPVs were declared carcinogenic (Group 1),
and an additional 13 were classified as either probably, or
possibly, carcinogenic (Group 2A and B) based on limited
evidence and/or their close phylogenetic placement with
other carcinogenic HPVs [40]. The oncogenic viruses in
each category are shown on the phylogenetic tree in figure 3.
(b) Beta human papillomaviruses
There has long been debate as to whether HPV types from the
beta genus are associated with skin keratinocyte carcinomas
(KC), in particular squamous cell carcinoma [41,42]. IARC
have declared that, at least in individuals with the genetic dis-
ease epidermodysplasia verruciformis (EV), two beta-HPV
types are possibly carcinogenic (Group 2). But so far there is
insufficient evidence for these viruses to be classified as carci-
nogenic in normal individuals [40]. It has been very difficult to
determine whether beta-HPVs are the etiological agent of KCs
because, unlike the oncogenic alpha-HPVs, they are not
required for maintenance of tumours [41]. Furthermore, they
are not found integrated in tumour cells, and no predominant
HPV type is consistently found associated with KC. Neverthe-
less, there is some evidence that beta-HPV could play a role in
the initiation of carcinogenesis [41].
(c) How do human papillomaviruses cause cancer?
Although many processes ultimately affect persistent HPV
infection, the E6 and E7 proteins are necessary and sufficient
for HPV-mediated oncogenesis. All HPV E6 and E7 proteins
bind to a plethora of cellular proteins and teasing apart the
precise interactions that make an E6 or E7 protein oncogenic
has not been simple [4346]. All papillomaviruses drive cel-
lular proliferation in the upper layers of an epithelium to
promote viral DNA amplification; however, the oncogenic
HPVs also promote cell-cycle entry, and inactivate cell-cycle
checkpoints, in the lower layers of an infected epithelium
[45]. The resulting genetic instability in these proliferating
cells has much more serious consequences compared to the
upper terminally differentiated cells. Key functions of the
HPV oncogenes are immune evasion, E7-mediated
HPV1
HPV63
HPV204
HPV41
HPV2
HPV27
HPV57
HPV3
HPV125
HPV28
HPV10
HPV94
HPV117
HPV78
HPV160
HPV29
HPV77
HPV71
HPV90
HPV106
HPV61
HPV72
HPV62
HPV81
HPV83
HPV102
HPV89
HPV84
HPV114
HPV86
HPV87
HPV18
HPV97
HPV45
HPV39
HPV68
HPV70
HPV85
HPV59
HPV54
HPV26
HPV69
HPV51
HPV82
HPV6
HPV11
HPV13
HPV44
HPV74
HPV32
HPV42
HPV7
HPV40
HPV43
HPV91
HPV16
HPV35
HPV31
HPV33
HPV58
HPV67
HPV52
HPV34
HPV73
HPV30
HPV53
HPV56
HPV66
HPV5
HPV47
HPV36
HPV143
HPV8
HPV99
HPV12
HPV105
HPV24
HPV98
HPV93
HPV14
HPV21
HPV20
HPV19
HPV25
HPV118
HPV124
HPV152
HPV9
HPV159
HPV111
HPV113
HPV122
HPV15
HPV80
HPV17
HPV37
HPV110
HPV22
HPV151
HPV100
HPV23
HPV120
HPV38
HPV145
HPV174
HPV104
HPV107
HPV49
HPV75
HPV76
HPV115
HPV92
HPV96
HPV150
HPV101
HPV103
HPV108
HPV109
HPV138
HPV139
HPV149
HPV155
HPV123
HPV170
HPV134
HPV201
HPV4
HPV65
HPV95
HPV158
HPV173
HPV205
HPV163
HPV144
HPV135
HPV179
HPV146
HPV161
HPV162
HPV166
HPV116
HPV129
HPV137
HPV126
HPV169
HPV171
HPV136
HPV141
HPV140
HPV202
HPV154
HPV128
HPV153
HPV60
HPV175
HPV156
HPV172
HPV184
HPV48
HPV200
HPV131
HPV50
HPV127
HPV199
HPV132
HPV148
HPV157
HPV165
HPV88
HPV112
HPV164
HPV119
HPV147
HPV168
HPV121
HPV180
HPV142
HPV130
HPV133
HPV167
HPV178
HPV197
g
a
m
m
a
b
e
t
a
a
l
p
h
a
mu
nu
Figure 3. Phylogenetic tree based on the L1 nucleotide sequence of HPVs. Group 1 oncogenic alpha-HPVs are shown in red, and Group 2 in orange.
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degradation of pRB family members, E6-mediated
degradation of p53 and PDZ binding domain proteins and
E6-mediated upregulation of telomerase [43– 46] and these
are listed in table 1. By contrast, the E6 and E7 proteins of the
beta-HPVs act as cofactors by inhibiting the cell-cycle arrest
and repair of UV-induced DNA damage [53], but they are
not required for maintenance of the tumour phenotype.
4. Natural history of human papillomavirus
infection and cancer progression
(a) Initial and persistent infection of the cervix
The oncogenic alpha-HPVs are sexually transmitted and
about 30% of young women become infected within 24
months of their first sexual exposure [54]. Infection can
result in mild cytological cervical abnormalities but about
90% will clear within 2 years [54]. However, long-term
persistent infection, beyond this time period, places individ-
uals at high risk for cervical intraepithelial neoplasia
(CIN). Figure 2 depicts oncogenic progression from infec-
tion through CIN stages 1– 3, and finally to invasive
cancer. It is estimated that about one-third of CIN3
lesions will progress to invasive cancer within 10 20
years [54].
(b) Immune detection and clearance
During the period of persistent infection, there is no apparent
immune detection of the virus [55]. This is in part, due to the
viral life cycle itself, which ensures that high levels of viral
activity occur only in the upper, differentiated cell layers
that are not exposed to immune defences. HPVs are also
0
2
4
6
8
10
12
14
16
18
total attributed to HPV
cervical
vaginal
vulvar
anal
rectal
oropharyngeal penile
women men
cancers in US per year (thousands)
HP V16 HP V18 HP V3 1 HPV3 3 HP V45 HP V52
HP V58 HP V35 HP V3 9 HPV5 1 HP V56 HP V59
cervical
vaginal
vulvar
penile
anal
rectal
oropharyngeal
(a)
(b)
(c)
Figure 4. Cancer statistics. (a) HPV-associated cancer incidence in the US 20082012 (data from Viens et al. [34]). (b) Distribution of oncogenic HPV types in
different cancers (data from Saraiya et al. [35]). (c) Relative proportion of HPV-associated cancer cases based on gender (data from Viens et al. [34]).
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well equipped to interfere with innate immune responses,
and to delay adaptive immune responses [55]. In fact, one
hypothesis is that the HPV oncogenes have evolved to
evade the intrinsic immune system, and that it is these prop-
erties that inadvertently promote oncogenesis [28]. At some
point during most HPV infections, the cell-mediated
immune system is alerted to the infection and this induces
regression of infected cells and lesions [55]. The role of the
humoral immune response in natural infection is not clear;
and many infected individuals do not seroconvert, leaving
them vulnerable to subsequent infection by the same virus
[54,55]. This is in contrast to the extremely high levels of humoral
antibodies, and protection, that results from immunization with
the HPV vaccine (see below) [56].
(c) Latency
A debated question, and closely related topic, is whether
HPVs enter a state of true latency ( presence of viral DNA
but no gene expression). It is challenging to detect low
copies of HPV DNA in the persistently infected lower
layers of an infected epithelium using in situ methods [57],
never mind the rare stem-like cell that might harbour latent
HPV. However, there is evidence from rabbit animal
models that PV infection can become latent, with no apparent
signs of infection [58,59]. Furthermore, latent infections can
be reactivated by mechanical or cellular stress [59,60]. If
these findings could be extrapolated to HPV infection, they
would help explain the second wave of HPV infection that
is often observed in older women [54]. These infections
could be due to reinfection (by the same HPV type) in
women who did not previously seroconvert in such a way
as to gain protection, or could be due to reactivation of a
latent infection.
(d) Natural history of oropharyngeal infections
The link between HPV infection and head and neck cancer
(HNSCC) was first noted over 30 years ago [61], and epide-
miological evidence demonstrated a causal association of
HPV in about 25% of these tumours [62]. HNSCC encom-
passes a wide range of tumours of the oral cavity, pharynx,
larynx, nasal passages, sinuses and salivary glands, but as
the prevalence of HPV association with each site has
become better characterized, the association of HPV with
oropharyngeal cancer (OPC) has risen to over 70%
(figure 4a). This association may reflect the susceptibility of
the epithelium in the tonsillar crypts to HPV infection and
persistence [63]. Moreover, HPV-positive OPCs are becoming
more prevalent than HPV-negative OPC tumours [64]. Men
are particularly susceptible to acquiring HPV infection by
oral sex, and slower to clear these acquired infections
([65,66] figure 4c). Increased vaginal exposure to HPV (as
measured by number of sexual partners) is inversely pro-
portional to the risk of oral HPV infection in women
[65,66]. This has led to the hypothesis that women are more
likely to develop a strong immune response resulting from
genital HPV exposure, which protects them from subsequent
oral infection [65,66].
(e) Multiple infections
Many studies detect the presence of multiple HPV types at the
same anatomical site within a single individual [35]. However,
there is strong evidence that each infection is clonal and results
from a single infected cell [67]. Even when multiple infections
are detected at a single site, they are due to independent bio-
logical infections of adjacent tissue and as stated by Quint
et al. ‘One virus, one lesion’ [67]. Moreover, epidemiological
studies show that multiple infections do not synergize to
increase the risk of oncogenesis [68].
(f) Cells vulnerable to infection and oncogenesis
Different HPV types have tropism for different types, and
anatomical sites, of cutaneous and mucosal epithelia.
Although not well understood, this tropism is thought to be
due to the transcriptional activity of each HPV type within
permissive cells, rather than the requirement for specific cell
surface receptors. All HPVs have a similar life cycle that
requires establishment of infection within an epithelial basal
cell, and generation of virus in the terminally differentiated
progeny of the infected cell. However, the situation is more
complex than this and the outcome of infection may
depend on the precise nature of the originally infected cell.
For example, most cases of cervical cancer arise from the cer-
vical transformation zone, a region of the cervix where the
ectocervix and endocervix meet and cells transition from
squamous to columnar epithelial cells [69]. This site could
be vulnerable to infection because the junction of two epi-
thelial types increases accessibility of the proliferative basal
cells. However, a discrete population of putatively residual
embryonic, squamocolumnar junction cells have been
identified and hypothesized to be the source of cells that
give rise to HPV-associated tumours [69,70]. Notably, similar
cellular transition zones exist in the oropharynx and anus,
Table 1. Major properties of the HPV E6 and E7 oncogenes.
oncogene property reference
E7 epigenetic reprogramming of cells by upregulation of KDM6A and KDM6B [25]
abrogation of pRb/E2F pathway by pRb degradation [47]
induction of DDR in differentiated cells to promote viral DNA amplification [48]
inhibition of innate immune response reviewed in [49]
E6 proteasome-mediated degradation of p53 [50]
induction of telomerase expression [51]
degradation of PDZ domain proteins involved in cell polarity reviewed in [52]
inhibition of innate immune response reviewed in [49]
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sites also highly susceptible to HPV oncogenesis, and similar
cell populations have been identified in the anorectal junction
[70]. Likewise, HPV oropharyngeal cancers typically arise
from the highly specialized reticulated epithelium that lines
the tonsillar crypts [64,71]. This specialized epithelium is in
close contact with cells of the immune system, and is a
frequent site of replication for several viruses.
The basal layers of stratified epithelia contain both
slow-cycling stem-like cells, as well as proliferating transit-
amplifying (TA) cells. The TA cells can divide both symmetrically
(to generate more basal TA cells) and asymmetrically, where
one of the daughter cells proceeds through the differentiation
and tissue renewal process. Infection of a TA basal cell could
result in a short-lived infection. In fact, modelling the stochas-
tic dynamics of basal cells predicts that over 80% of infections
could spontaneously clear as infected cells mature [72].
Long-term, persistent infection most probably requires
infection of a slow-cycling stem cell. Moreover, infection of
these slow-cycling cells could promote latency [73].
(g) Genetic susceptibility to human papillomavirus
infection
The importance of the immune system in controlling HPV
infection is very evident in individuals with specific immuno-
deficiencies [74]. Individuals with EV, WHIM (warts,
hypogammaglobulinemia, infections and myelokathexis) syn-
drome, GATA2 or DOCK8 deficiencies, and other syndromes
are highly susceptible to pathological HPV infection by viral
types that are often asymptomatic or self-limiting in normal
individuals [74]. In some cases, these infections can progress
to anogenital or skin cancer [74]. The latter observation has
led the IARC to declare two beta-HPV types possibly carcino-
genic (Group 2) in the genetic background of EV. Individuals
with Fanconi anaemia (FA) have defects in DNA repair and
are highly susceptible to HPV infections and carcinomas in
sites usually associated with HPV oncogenesis. However,
many of these cancers are HPV-negative; it seems that HPV
activates the defective FA pathway, causing great genomic
instability, and eventually rendering the cells no longer
dependent on HPV to maintain the tumour phenotype [75].
(h) Carcinogenic progression
Oncogenic E6 and E7 manipulate many cellular pathways to
induce an environment that supports the viral life cycle, but
inactivation of crucial cell-cycle checkpoints lead to genetic
instability, accumulation of mutations in cellular genes and
malignant progression. There are no mutations found consist-
ently in all HPV-associated cancers, but there are frequent
mutations in the PI3 K pathway, as well as in receptor tyrosine
kinases, and genes related to keratinocyte differentiation and
the immune response [76–78].
The viral genome in most, though not all, HPV-associated
cancers is found integrated into the host genome. Integration
can disrupt E2-mediated viral gene expression, thus promot-
ing genomic instability by deregulating E6/E7 gene
expression. E6/E7 are also expressed from integrated gen-
omes as a viral-cellular fusion transcript that is often more
stable than the viral mRNA [79]. There is also powerful selec-
tion for epigenetic events that promote E6/E7 expression
[80,81]. Integration is thought to be an inadvertent event,
but HPVs replicate adjacent to regions of the host DNA
undergoing replication stress (fragile sites) and this could
promote integration into these loci [82].
(i) Multifactorial nature of human papillomavirus
persistence and oncogenesis
Infection with an oncogenic HPV does not by itself place indi-
viduals at high risk of cancer, as most individuals clear
infections within 1– 2 years. However, long-term persistence
of infection is key to the development of HPV-mediated
cancer [83]. Persistence and oncogenesis are the cumulative
result of many factors listed here: infected cells with
stem-cell-like properties might be necessary to sustain a
long-lived infection; the virus must establish a persistent infec-
tion in the face of intrinsic anti-viral factors; the HPV genome
must be capable of robust long-term replication; the oncogenes
of the virus need to inactivate cellular checkpoints; the virus
must evade the cell-mediated immune system, which could
recognize and clear the infection; stochastic genetic and epi-
genetic events can result in dysregulation of E6/E7
expression, and/or integration of the virus; and the infected
cells might acquire properties that result in invasive cancer.
On a positive note, many of these steps could be manipulated
to intervene in the infectious process.
5. Therapeutics
HPV vaccines have been extremely successful from both a
scientific and clinical viewpoint, and there is now a vaccine
that protects against nine of the most prevalent HPVs associ-
ated with cancer and genital warts [56,84]. However, uptake
has been slow in some countries, and the current vaccines are
expensive and difficult to distribute to the developing world.
For individuals already infected, the Pap smear test, intro-
duced in 1941, has been very successful in screening for
surgically treatable HPV-associated cervical lesions, but
there is not an equivalent test for OPC because of the inac-
cessibility of the infection site. There are a number of
potential therapeutic targets for HPV disease. Most infections
are naturally cleared by cell-mediated immunity, and so
therapeutic vaccines, or other immunomodulatory interven-
tions have much potential [77]. Efficient partitioning of the
viral genome is essential for persistent infection and disrup-
tion of this process could ‘cure’ genomes and resolve early
lesions. HPV manipulates epigenetic modification of host
chromatin [25] and integrated viral DNA is regulated by
chromatin and DNA modifications [80,81], and so the rapidly
expanding field of pharmacological modulation of epigen-
omes [85] could have great benefits for HPV-associated
disease. Despite the accumulation of cellular mutations in
HPV-associated cancers, the cells remain ‘addicted’ and
dependent on continued expression of the viral oncogenes,
providing another Achilles heel [44]. Strong support of
these basic research areas will provide further insight into
therapeutic interventions of HPV-associated disease.
Data accessibility. This article has no additional data.
Competing interests. I have no competing interests.
Funding. Alison McBride is supported by the Intramural Research
Program of the NIAID, NIH.
Acknowledgements. I apologize to colleagues whose primary work I
could not cite because of the breadth of the topic. Each review
cited here was carefully chosen and I strongly encourage readers to
read both these reviews and the primary work cited within.
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... More than 200 Human Papillomavirus (HPV) types have been identified so far, which are divided in 5 genera (Alpha, Beta, Gamma, Delta, Mu and Nu) according to their nucleotide sequence of L1 gene (de Villiers, 2013;Mühr et al., 2018) (Figure 1) and are further classified into mucosal or cutaneous depending on their replication site. They are also subdivided between low and high-risk viruses, based on their oncogenic potential, particularly for the Alpha HPV (Bzhalava et al., 2015;Egawa et al., 2017;McBride, 2017). ...
... Beta, Gamma, Nu and Mu target cutaneous epithelial sites. Adapted from (McBride, 2017;Doorbar, 2018). 1 4 As for many other viruses that have co-evolved with their hosts, most HPV infections are asymptomatic. Indeed, many HPV types are detected in healthy individuals and are associated with non-apparent infections or manifest as benign lesions (Alizon et al., 2017). ...
... In addition, integration of HPV genome can also contribute to malignant progression by disrupting the expression of cellular genes, for example, the MYC gene locus. There is not a clear signature for HPV integration sites, but integration usually occurs at fragile sites, with inherent genomic instability and susceptible to replication stress as well as transcriptionally active sites (McBride, 2017). 1 18 Regulation of E6/E7 expression also depends on the nature of the infected cell since some epithelial sites allow for a controlled expression while others favour deregulation. For example, infections at the ectocervical pluristratified epithelium usually results in productive infections with ordered viral gene expression and are ranked as CIN1. ...
Thesis
Human papillomavirus (HPV) are part of our virome and infect cutaneous and mucosal sites. Most infections are asymptomatic or only cause benign lesions that are controlled by the host defence mechanisms, which take place both at the epithelial and the immune system levels. However, persistent infections with certain mucosal HPV types at high-risk for cancer development, cause virtually all cases of cervical cancers, a majority of anogenital cancers and an increasing proportion of oropharyngeal cancers. Prophylactic vaccines are efficient in preventing mucosal HPV types-associated lesions but currently, there is no antiviral treatment for an established HPV infection. In this doctoral thesis, we aimed at investigating host factors involved in HPV life cycle and carcinogenesis at two levels: the infected keratinocyte and the immune system. Studies in the context of certain immunodeficient patients (WHIM syndrome, WS) with selective susceptibility to HPV pathogenesis have identified the CXCL12 chemokine and its classical G protein-coupled receptor CXCR4 (whose mutations are causing the WS) as host susceptibility factors that act as gatekeepers of HPV life cycle. CXCL12/CXCR4 together with ACKR3, the second receptor of CXCL12 with an atypical decoy activity, can modulate both epithelial and immune cell anti-viral responses. Therefore, we first investigated the intrinsic contribution of ACKR3 to HPV life cycle in 3D human epithelial cell cultures (3D-EpC), the sole model allowing for HPV replication. Our results indicate that enhanced ACKR3 activity displays pro-oncogenic potential as it shifts HPV productive life cycle toward oncogenesis and that blocking ACKR3 could be an attractive therapeutic approach to favour HPV replication. In addition, we have studied the functional consequences of the productive HPV life cycle in cell-cell communication, being pioneers in setting up FLIP technique in 3D-EpC. Lastly, we investigated the impact of CXCR4 WS-mutation at the cutaneous immune cell level in the context of HPV-induced carcinogenesis. We have thus gained insights into the role of CXCR4 in dendritic cell and Langerhans cell distribution, phenotype and migration and how their deregulation in the context of the WS could account for the selective susceptibility of WS patients to HPV pathogenesis. In conclusion, this work provides new insights into HPV-host interactions at the epithelial and immune cell levels. We have unravelled the central role of ACKR3 in keratinocyte intrinsic response against HPV and deepen our knowledge on the role of CXCL12/CXCR4 in skin immunity in health and in HPV carcinogenesis.
... As partículas virais são montadas na superfície e liberadas do epitélio como escamas carregadas de vírus. Essa estratégia de infectar células auto renováveis garante a persistência do vírus a longo prazo, enquanto se acredita que o confinamento de altos níveis de proteínas virais às camadas mais diferenciadas de lesões ajude o vírus a evitar a detecção pelo sistema imunológico(McBride, 2017).Os cirurgiões dentistas, enquanto profissionais de saúde, devem atuar fortemente na detecção destes fatores que são implicados na etiologia e patogênese destas lesões com o intuito de contribuir para a detecção precoce e prevenção dessas lesões, especialmente em pacientes jovens sem risco ou hábitos tradicionalmente ligados ao câncer bucal, como o consumo de tabaco e/ou álcool ...
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Os fatores de risco para o desenvolvimento do câncer de boca têm sido muito questionados atualmente, devido ao grande aumento de sua prevalência entre a população. Existem vários tipos de fatores de risco, sendo estes, tabagismo, etilismo, infeçção pelo vírus do HPV, exposição solar desprotegida, dieta e má higiene bucal. Um dos fatores etiológicos que tem se mostrado com uma maior predisposição para a lesão maligna é o tabagismo e etilismo, principalmente com a associação simultânea (sinergismo). O cirurgião dentista possui um papel fundamental na prevenção e diagnóstico do câncer bucal, além de conscientizar o paciente em relação aos seus hábitos e cuidados com a saúde, especialmente as pessoas que dispõe dos fatores etiológicos. Este trabalho objetiva trazer informações a respeito dos principais fatores de risco que atuam no desenvolvimento da lesão maligna na cavidade bucal, o qual poderá servir como base informacional acerca deste tema para acadêmicos de odontologia bem como para profissionais da área. Foi realizada uma revisão da literatura narrativa descritiva, utilizando como base bibliográfica artigos científicos publicados entre os anos de 2011 a 2022, disponíveis em banco de dados online como PubMed, Scielo, Google Acadêmico, INCA, sendo que os artigos se encontram nos idiomas português e inglês.
... HPV is a member of the Papillomaviridae family, which is currently split into 16 genera, of which 5 genera contain members that infect humans, namely Alpha-, Beta-, Gamma-, Mupa-, and Nupapapillomavirus [6]. Over 200 distinct kinds of HPV have been found [7]. Based on the likelihood of cancer development, HPV is categorized into two primary groups: "high-risk HPVs" (Hr-HPVs) and "low-risk HPVs" (Lr-HPVs). ...
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Human papillomavirus type 16 (HPV16) and/or high-risk (Hr-) HPV are the main causes of cervical cancer. Another element that may contribute to the development of cervical cancer is the microbiota. To date, no study has investigated the entire cervical microbiome, which consists of bacteria, fungi, and viruses. In this study, cervical samples with different histopathology (CIN1, CIN2, and CIN3), with or without HPV16 and Hr-HPVs infection, were enrolled. From bacterial community analysis, 115 bacterial species were found and separated into 2 distinct categories based on Lactobacillus abundance: Lactobacilli-dominated (LD) and non-Lactobacilli-dominated (NLD) groups. The LD group had significantly less bacterial diversity than the NLD group. In addition, the variety of bacteria was contingent on the prevalence of HPV infection. Among distinct histological groups, an abundance of L. iners (>60% of total Lactobacillus spp.) was discovered in both groups. A few fungi, e.g., C. albicans, were identified in the fungal community. The viral community analysis revealed that the presence of HPV considerably reduced the diversity of human viruses. Taken together, when we analyzed all our results collectively, we discovered that HPV infection was a significant determinant in the diversity of bacteria and human viruses in the cervix.
... This phenomenon leads to the misappropriation of the cell cycle of the host. A high prevalence of HPV-related ASCC is reported in human immunodeficiency virus (HIV)-infected or iatrogenically immunosuppressed patients, as well as in men who have sex with men (MSM), while precursors of this malignancy are considered high-grade squamous intraepithelial lesions (HSILs), which can progress to ASCC, due to impaired immune responses in the anal mucosa even after treatment with electrocautery ablation [140][141][142]. ...
Article
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The development of cancer is a multifactorial phenomenon, while it constitutes a major global health problem. Viruses are an important factor that is involved in tumorigenesis and is associated with 12.1% of all cancer cases. Major examples of oncogenic viruses which are closely associated with the digestive system are HBV, HCV, EBV, HPV, JCV, and CMV. EBV, HPV, JCV, and CMV directly cause oncogenesis by expressing oncogenic proteins that are encoded in their genome. In contrast, HBV and HCV are correlated indirectly with carcinogenesis by causing chronic inflammation in the infected organs. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as several growth factors, cytokines, and other tumor-secreted molecules that play a key role in tumor growth, progression, and migration, while they are closely interrelated with the virus. The presence of T-regulatory and B-regulatory cells in the tumor microenvironment plays an important role in the anti-tumor immune reaction. The tumor immune microenvironments differ in each type of cancer and depend on viral infection. The alterations in the immune microenvironment caused by viruses are also reflected in the effectiveness of immunotherapy. The present review aims at shedding light on the association between viruses and digestive system malignancies, the characteristics of the tumor immune microenvironment that develop, and the possible treatments that can be administered.
... While HPV and HTLV1 are both oncogenic viruses, they operate in distinct tissues, respectively epithelial cells 35 and T-lymphocytes 36,37 . Upon infection, their oncoproteins thus encounter distinct host proteomes. ...
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Human protein networks have been widely explored but most binding affinities remain unknown, hindering quantitative interactome-function studies. Yet interactomes rely on minimal interacting fragments displaying quantifiable affinities. Here, we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer. We calculate interactomic distances, identify hot spots for viral interference, generate binding profiles and specificity logos, and explain selected cases by crystallographic studies. Mass spectrometry experiments on cell extracts and literature surveys show that quantitative fragmentomics effectively complements protein interactomics by providing affinities and completeness of coverage, putting a full human interactome affinity survey within reach. Finally, we show that interactome hijacking by the viral PBM of human papillomavirus E6 oncoprotein substantially impacts the host cell proteome beyond immediate E6 binders, illustrating the complex system-wide relationship between interactome and function. Protein networks have been widely explored but most binding affinities remain unknown, limiting the quantitative interpretation of interactomes. Here the authors measure affinities of 65,000 interactions involving human PDZ domains and target sequence motifs relevant for viral infection and cancer.
... HPV belongs to family Papillomaviridae and currently divided into 5 genera, namely Alpha-, Beta-, Gamma-, Mupaand Nupapapillomavirus containing members, all of which can infect humans (Brooks et al., 2013). To this date, more than 200 HPV types have been identified (McBride, 2017). In the Alphapapillomavirus genus, HPVs are divided into two major groups -high-risk HPVs (Hr-HPVs) and low-risk HPVs (Lr-HPVs) -based on the cancer risk associated with their infection. ...
Article
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Cervical cancer is the fourth most common cancer in women worldwide. More than 90% of cases are caused by the human papillomavirus (HPV). Vaccines developed only guard against a few HPV types and do not protect people who have already been infected. HPV is a small DNA virus that infects the basal layer of the stratified epithelium of the skin and mucosa through small breaks and replicates as the cells differentiate. The mucosal types of HPV can be classified into low-risk and high-risk groups, based on their association with cancer. Among HPV types in high-risk group, HPV type 16 (HPV-16) is the most common, causing 50% of all cancer cases. HPV infection can occur as transient or persistent infections, based on the ability of immune system to clear the virus. Persistent infection is characterized by the integration of HPV genome. HPV-16 exhibits a different integration pattern, with only 50% reported to be integrated at the carcinoma stage. Replication of the HPV genome depends on protein E1, an ATP-dependent helicase. E1 is essential for the amplification of the viral episome in infected cells. Previous studies have shown that E1 does not only act as a helicase protein but is also involved in recruiting and interacting with other host proteins. E1 has also been deemed to drive host cell proliferation. Recent studies have emphasized the emerging role of HPV E1 in cervical carcinogenesis. In this review, a possible mechanism by which E1 drives cell proliferation and oncogenesis will be discussed.
... Of the approximately 200 genotypes of HPV, subdivided into 14 species, about 40 can infect the epithelial cells (skin or mucous membranes) of the anogenital regions and other areas [3]. Differentiation into types is made based on the characteristics of the L1 protein [4]. HPV was the first virus to be recognized as responsible for cervical cancer (CC). ...
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The heterogeneity of the cervico-vaginal microbiota can be appreciated in various conditions, both pathological and non-pathological, and can vary according to biological and environmental factors. Attempts are still in course to define the interaction and role of the various factors that constitute this community of commensals in immune protection, inflammatory processes, and the onset of precancerous lesions of the cervical epithelium. Despite the many studies on the relationship between microbiota, immunity, and HPV-related cervical tumors, further aspects still need to be probed. In this review article, we will examine the principal characteristics of microorganisms commonly found in cervico-vaginal specimens (i) the factors that notoriously condition the diversity and composition of microbiota, (ii) the role that some families of organisms may play in the onset of HPV-dysplastic lesions and in neoplastic progression, and (iii) possible diagnostic-therapeutic approaches.
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The human papillomavirus (HPV) is one of the most common sexually transmitted infections worldwide. The risk of being infected at least once in a lifetime among both men and women is estimated to be 50%. Although the majority of HPV infections are asymptomatic and improve within 2 years, approximately 10% of individuals develop a persistent infection and have an increased risk of developing carcinomas. The association of HPV and genital cancer is well established. However, there is evidence that HPV may also be associated with other cancers, including those of the gastrointestinal system. The aim of this review is to organize the current evidence of associations between HPV infections and oropharyngeal and gastrointestinal cancers, including the following: oropharyngeal, esophageal, gastric, colorectal, and anal cancers. A comprehensive review of the most up-to-date medical literature concluded that an HPV infection might have a role in the oncogenesis of gastrointestinal tract cancers. HPV may have a causal relationship with oropharyngeal and esophageal squamous cell cancers. However, the association between HPV and gastric and colorectal cancers is weaker. The development of cancer in the oropharyngeal and gastrointestinal tract is usually multifactorial, with HPV having a role in at least a subset of these cancers. HPV infections pose a big challenge due to their burden of infection and their oncogenic potential.
Article
The incidence of cervical cancer has increased worldwide, with 604 000 new cases occurring in 2020 causing 342 000 deaths. It is now the fourth leading cause of cancer in low and middle-income countries. A significant number of these cancers are directly associated with human papilloma viruses (HPVs), with 50% of high-grade cervical cancers arising due to HPV Types 16 and 18. Whilst cervical screening programmes aim to detect and treat cancers earlier, the HPV vaccination programme in the UK is a cost-effective method in preventing cervical cancer and also other HPV-associated cancers such as anal, penile and oropharyngeal cancers. The aim of this article is to provide an overview of HPV, the cancers associated with it and the role of the current UK vaccination programme.
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Invasive ductal carcinoma (IDC) , a cancer that arises from the epithelial cells which line the ducts and lobules of the breast, is distinct from other cancers in that it lacks the morphological characteristics which would allow it to be classified as any specific histological type. The cancer could be classified as invasive ductal carcinoma-not otherwise specified if the specific subtype comprises less than ten percent of the total tumor volume. This could be classified as a mixed tumor if the specific subtype comprises more than this percentage of the tumor's volume. The study aimed to detect the presence of human papilloma virus (HPV) LMP1 in a group of Iraqi women diagnosed with IDC and to correlate expression patterns with age of the participants and with the grade and stage of cancer. A total of 30 formalin-fixed paraffin-embedded tissue of IDC biopsy samples and 29 FFPE tissues of fibroadenoma controls were collected and tested to detect the presence of HPV LMP1 using immunohistochemistry. LMP1 expression was found in 40% of cases and in 1% of the control specimens. The expression pattern of LMP1 was determined to be statistically significant when correlated with age, grade and stage. The immunohistochemistry was sensitive technique in the detection of HPV. The study reveals that the LMP1 was over expressed in our population cohort.
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In cancer cells associated with human papillomavirus (HPV) infections, the viral genome is very often found integrated into the cellular genome. The viral oncogenes E6 and E7 are transcribed from the viral promoter, and integration events that alter transcriptional regulation of this promoter contribute to carcinogenic progression. In this study, we detected highly enriched binding of the super-enhancer markers Brd4, MED1, and H3K27ac, visible as a prominent nuclear focus by immunofluorescence, at the tandemly integrated copies of HPV16 in cells of the cervical neoplasia cell line W12 subclone 20861. Tumor cells are often addicted to super-enhancer-driven oncogenes and are particularly sensitive to disruption of transcription factor binding to the enhancers. Treatment of 20861 cells with bromodomain inhibitors displaced Brd4 from the HPV integration site, greatly decreased E6/E7 transcription, and inhibited cellular proliferation. Thus, Brd4 activates viral transcription at this integration site, and strong selection for E6/E7 expression can drive the formation of a super-enhancer-like element to promote oncogenesis. IMPORTANCE Oncogenic human papillomaviruses play an essential role in the development of cervical cancer, and growth of these cancer cells requires continued expression of the viral E6 and E7 oncogenes. Integration of the virus into the host genome often results in deregulation of E6 and E7 expression, which provides a selective growth advantage and increases genetic instability of infected cells. We show here that tandemly integrated copies of the viral genome can form a super-enhancer-like element that drives E6/E7 transcription. Targeted disruption of factors binding to this element decreases viral transcription and causes cell death. Thus, cancer cells that harbor integrated HPV could be targeted by therapeutics that disrupt super-enhancer function.
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It is becoming clear that, in addition to gene gain, the loss of genes may be an important evolutionary mechanism for many organisms. However, gene loss is often associated with an increased mutation rate, thus quickly erasing evidence from the genome. The analysis of evolutionarily related sequences can provide empirical evidence for gene loss events. This paper analyzes the sequences of over 300 genetically distinct papillomaviruses and provides evidence for a role of gene loss during the evolution of certain papillomavirus genomes. Phylogenetic analysis suggests that the viral E6 gene was lost at least twice. Despite belonging to distant papillomaviral genera, these viruses lacking a canonical E6 protein may potentially encode a highly hydrophobic protein from an overlapping open reading frame, which we designate E10. Evolutionary pressure working on this alternative frame, may explain why, despite having lost the E6 open reading frame between 20 and 60 million years ago, evidence of an E6-like protein is conserved.
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Background: Infections with certain viruses, bacteria, and parasites are strong risk factors for specific cancers. As new cancer statistics and epidemiological findings have accumulated in the past 5 years, we aimed to assess the causal involvement of the main carcinogenic agents in different cancer types for the year 2012. Methods: We considered ten infectious agents classified as carcinogenic to human beings by the International Agency for Research on Cancer. We calculated the number of new cancer cases in 2012 attributable to infections by country, by combining cancer incidence estimates (from GLOBOCAN 2012) with estimates of attributable fraction (AF) for the infectious agents. AF estimates were calculated from the prevalence of infection in cancer cases and the relative risk for the infection (for some sites). Estimates of infection prevalence, relative risk, and corresponding 95% CIs for AF were obtained from systematic reviews and pooled analyses. Findings: Of 14 million new cancer cases in 2012, 2·2 million (15·4%) were attributable to carcinogenic infections. The most important infectious agents worldwide were Helicobacter pylori (770 000 cases), human papillomavirus (640 000), hepatitis B virus (420 000), hepatitis C virus (170 000), and Epstein-Barr virus (120 000). Kaposi's sarcoma was the second largest contributor to the cancer burden in sub-Saharan Africa. The AFs for infection varied by country and development status—from less than 5% in the USA, Canada, Australia, New Zealand, and some countries in western and northern Europe to more than 50% in some countries in sub-Saharan Africa. Interpretation: A large potential exists for reducing the burden of cancer caused by infections. Socioeconomic development is associated with a decrease in infection-associated cancers; however, to reduce the incidence of these cancers without delay, population-based vaccination and screen-and-treat programmes should be made accessible and available. Funding: Fondation de France.
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Importance: Lymphocystis disease affects marine and freshwater fish species worldwide. It is characterized by the appearance of papilloma-like lesions on the skin that contain heavily enlarged cells (lymphocysts). The causative agent is the lymphocystis disease virus (LCDV), a large icosahedral virus of the family Iridoviridae In the Mediterranean area the gilthead seabream (Sparus aurata), an important farmed fish, is frequently affected. Using next generation sequencing, we have identified within lymphocystis lesions the concurrent presence of a further LCDV species (LCDV-Sa) as well as two novel viruses. These are members of polyoma- and papillomavirus families and here we report them to be frequently associated with the presence of lymphocysts in affected fish. Because papillomaviruses had not been described in fish before, these findings support a more ancient origin of this virus family than previously thought and evolutionary implications are discussed.
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What is already known about this topic? Persistent infections with human papillomavirus (HPV) can cause carcinomas of the cervix, and squamous cell cancers of the vulva, vagina, penis, anus, rectum, and oropharynx. Many of these cancers are preventable with currently available vaccines; effective screening programs can identify cervical precancers for treatment before they can progress to cancer. What is added by this report? An average of 38,793 HPV-associated cancers (11.7 per 100,000 persons) were diagnosed annually in the United States during 2008-2012, including 23,000 (13.5) among females and 15,793 (9.7) among males. Among these cancers, CDC estimates that 30,700 (79%) can be attributed to HPV, and 28,500 of these are attributable to HPV types that are preventable with the 9-valent HPV vaccine. What are the implications for public health practice? Full vaccination coverage of the U.S. population could prevent future HPV-attributable cancers and potentially reduce racial and ethnic disparities in HPV-associated cancer incidence. Ongoing surveillance for HPV-associated cancers using high-quality population-based registries is needed to monitor trends in cancer incidence that might result from increasing use of HPV vaccines and changes in cervical cancer screening practices. © 2016, Department of Health and Human Services. All rights reserved.
Article
The life cycle of human papillomaviruses (HPV) is tightly regulated by the differentiation state of mucosal and cutaneous keratinocytes. To counteract viral infection, constitutively expressed cellular factors, which are defined herein as restriction factors, directly mitigate viral gene expression and replication. In turn, some HPV gene products target these restriction factors and abrogate their anti-viral effects to establish efficient gene expression and replication programs. Ironically, in certain circumstances, this delicate counterbalance between viral gene products and restriction factors facilitates persistent infection by HPVs. This review serves to recapitulate the current knowledge of nuclear restriction factors that directly affect the HPV infectious cycle.
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The innate immune response constitutes the first line of defense against infections by pathogens. Successful pathogens such as human papillomaviruses (HPVs) have evolved mechanisms that target several points in these pathways including sensing of viral genomes, blocking the synthesis of interferons and inhibiting the action of JAK/STAT transcription factors. Disruption of these inhibitory mechanisms contributes to the ability of HPVs to establish persistent infections, which is the major etiological factor in the development of anogenital cancers. Interestingly, HPVs also positively activate several members of these pathways such as STAT-5 that are important for their differentiation-dependent life cycle. STAT-5 activation induces the ATM and ATR DNA damage response pathways that play critical roles in HPV genome amplification. Targeting of these pathways by pharmaceuticals can provide novel opportunities to inhibit infections by these important human pathogens.
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The aetiologic association between infection with certain human papillomavirus (HPV) types, high-grade squamous neoplasia, and cancer at different epithelial sites is well established. In this review we briefly discuss recent breakthroughs in the regulation of squamous epithelia in homeostasis and disease, and provide a view of how these discoveries modify our understanding of how HPV-induced neoplasia in squamous epithelia is triggered. Taken together, these observations highlight how HPVs have evolved the ability to inactivate the products of genes that are frequently mutated in non-HPV-associated pre-neoplasia and squamous cell carcinoma of sun-exposed skin, and introduce a Darwinian model of clonal evolution of HPV-infected cells. These concepts are considered against our current understanding of transformation zones where HPV-associated cancers occur more frequently, and other sites of non-productive (or abortive) HPV infection.
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Human papillomaviruses (HPVs) are the causative agents of 5% of all human cancers, with cervical cancer being the most important. Two viral oncoproteins, E6 and E7, are essential for the development and maintenance of malignancy. Both proteins function by targeting critical pathways that are essential for maintaining cellular homeostasis. As a consequence of these activities, this produces an environment that is favourable for the normal viral life cycle, but when perturbed, can result in the initiation of changes to the host cell, which ultimately results in the development of a malignancy. In this review we discuss the role of these different functions of the viral oncoproteins during the viral life cycle and carcinogenesis, with an emphasis on how induction of DNA damage by the viral oncoproteins, in conjunction with the stem like nature of the target cells, can ultimately result in the development of cancer.
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Background HPV-positive oropharynx cancer is frequently characterized as a disease of never-smokers due to higher HPV prevalence in oropharynx tumors among never-smokers than ever-smokers. We sought to estimate the burden (incidence rates and case counts) of HPV-positive oropharynx cancers among never, former, and current smokers in the US population by combining data from several sources. Methods We decomposed the SEER population-level incidence of oropharynx cancers into rates among never-, former-, and current-smokers using a formula based upon rate ratios (RR) for the smoking-oropharynx cancer association (NIH-AARP cohort study) and smoking prevalence in the U.S. population (NHANES 2007/2008). These rates were multiplied by smoking strata-specific HPV prevalence in oropharynx cancer patients (RTOG0129) to estimate incidence of HPV-positive and HPV-negative oropharynx cancers, which were applied to the US population of smokers to calculate annual case counts. Analyses were conducted overall and gender-stratified. Results The incidence of HPV-positive oropharynx cancers was significantly higher among ever versus never-smokers in the US population aged 20+ years during 2007/2008 (RR = 1.81; 95%CI = 1.32–2.47), including significantly higher incidence in current smokers (RR = 2.26; 95%CI = 1.60–3.21) and former smokers (RR = 1.38; 95%CI = 1.02–1.85). Of the estimated 6677 (5418 in men and 1259 in women) annually incident HPV-positive oropharynx cancers in the U.S during 2007/2008, 63.3% arose among ever smokers and 36.7% among never-smokers (p < 0.001). In both men and women, incidence rates and annual cases of HPV-positive oropharynx cancers were higher in ever smokers versus never smokers. Conclusions The population-level burden of HPV-positive oropharynx cancers is significantly higher among ever-smokers than never-smokers in the U.S.