rEVIEWS - Advances in Clinical and Experimental Medicine

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Adv Clin Exp Med 2012, 21, 2, 235–244
ISSN 1899–5276
© Copyright by Wroclaw Medical University
Urszula Ciesielska, Katarzyna Nowińska, Marzena Podhorska-Okołów,
Piotr Dzięgiel
The Role of Human Papillomavirus
in the Malignant Transformation
of Cervix Epithelial Cells and the Importance
of Vaccination Against This Virus*
Rola HPV w mechanizmie transformacji nowotworowej
komórek nabłonka szyjki macicy oraz znaczenie szczepionki
przeciwko temu wirusowi
Department of Histology and Embryology, Wroclaw Medical University
Abstract
Human papillomavirus (HPV) belongs to the diverse group of sexually transmitted viruses that manifest affinity
to the squamous epithelia of the skin and mucous membranes. Over 100 types of HPV have been described and
identified in human tissues, and it has been proved that persistent infection with high-risk types of the virus (types
16 and 18 in particular) could lead to cervical cancer. High-risk HPV types have been found in approximately 70%
of all cases of cervical cancer worldwide. The aim of this study was to describe the role of HPV in the process of
neoplastic transformation in epithelial cells and to emphasize the prophylactic significance of vaccinations against
the virus (Adv Clin Exp Med 2012, 21, 2, 235–244).
Key words: human papillomavirus (HPV), neoplastic transformation, cancer of uterine cervix, vaccine against HPV.
Streszczenie
Wirus brodawczaka ludzkiego (HPV – human papillomavirus) jest zaliczany do zróżnicowanej grupy wirusów
przenoszonych drogą płciową, wykazujących powinowactwo do nabłonka wielowarstwowego płaskiego skóry oraz
błon śluzowych człowieka. Do chwili obecnej wyodrębniono ponad 100 typów tego wirusa i udowodniono, iż
przetrwałe zakażenie jego onkogennymi typami (zwłaszcza 16 i 18) może prowadzić do rozwoju raka szyjki macicy.
Obecność tych typów HPV stwierdzono w około 70% przypadków raka szyjki macicy na świecie. Celem pracy było
omówienie roli HPV w procesie transformacji nowotworowej komórek nabłonkowych oraz podkreślenie znaczenia
profilaktycznego zastosowania szczepionki przeciw temu wirusowi (Adv Clin Exp Med 2012, 21, 2, 235–244).
Słowa kluczowe: wirus brodawczaka ludzkiego (HPV), transformacja nowotworowa, rak szyjki macicy, szczepionka przeciw HPV.
Human papillomavirus (HPV) represents
a group of widely diversified viruses that are implicated in the etiology of uterine cervix cancer. In 2008,
the German scientist Harald zur Hausen was awarded the Nobel prize in medicine for the discovery of
the human papillomavirus. The results of his studies
confirmed the role of HPV in the etiology of uterine
cervix cancer, contributed to the development of new
tests permitting an early diagnosis of cervical carcinoma and established new directions for prophylaxis
against this cancer. Prof. zur Hausen’s studies made
it possible to develop a prophylactic vaccine against
HPV infection and therefore lowering the risk of developing cancer of the uterine cervix [1–3].
*This study was supported by Wrocław Medical University (research grant number 1421).
236
HPVs demonstrate a specific tropism to cells
of the squamous epithelium of the skin and mucous membranes in humans and several animal
species [4]. They may penetrate and infect cells in
basal and parabasal layers of the epithelium but the
full developmental cycle and production of infectious progeny particles takes place only in differentiated keratinocytes [5]. Over 100 types of HPV
are known, of which about 40 infect the mucosal
epithelia of the anogenital regions [6, 7]. They have
been divided into three groups, depending on their
oncogenic potential [8, 9]:
1. HPVs of a low oncogenic potential – HPV
types 6, 11, 42, 43 and 44;
2. HPVs of a moderate oncogenic potential
– HPV types 31, 33, 35, 39, 45, 51, 52 and 56;
3. HPVs of a high oncogenic potential – HPV
types 16 and 18.
Most types of HPV are responsible for the development of benign dermal lesions in the form of
dermal warts and condylomas, warts of the genital
regions. However, clinical data also indicate a relationship between infection with the virus and preneoplastic lesions and tumors of the mucosa of the
genital regions and anus. High-risk HPVs (types
16 and 18) are associated with malignant lesions
of the genital regions. HPV 16 is the most prevalent of the high-risk types, found in about 54% of
cervical cancer cases, while HPV 18 is detected in
around 16% of the cases [10].
The HPV Genome Structure
and Functioning
Human papillomavirus belongs to the Papillomaviridae family. These are small non-enveloped
double-stranded DNA viruses with a genome of
approximately 8000 base pairs [3]. All the viral
genes are located on a single DNA strand, which is
transcriptionally active. They are accumulated in
two open reading frames (ORFs) [8]. In the HPV
genome three regions can be distinguished:
– the early region (E) – coding for early control proteins (E1, E2, E4, E5, E6 and E7), which
are responsible for the persistence of the viral genome in a cell, its replication and for the neoplastic
transformation of host cells; they are expressed in
all phases of the cell cycle;
– the late region (L) – coding for structural
proteins: major and minor capsid proteins (L1 and
L2, respectively);
– the long control region (LCR) – not coding
for structural proteins, but performing a controlling function in the expression and replication of
the viral genome.
U. Ciesielska et al.
Proteins, of the E1 and E2 regions are responsible for the initiation of viral DNA replication, due
to their ability to bind transcription factors. They
play key roles in the transcriptional regulation and
replication of viral DNA [3, 7]. Proteins of the E2
region bind to DNA sequences in the control region and perform the function of activator or repressor of viral gene transcription. E4 protein has
ability to bind keratin filaments, inducing changes
in keratinocytes; and to release viral progeny particles from cells, resulting in the formation of koilocytes (cells with a characteristic bright perinuclear
halo and a clearly marked cell membrane, resulting
from the proliferation of HPV). E5, E6 and E7 are
viral proteins with oncogenic properties, responsible for the neoplastic transformation of cells. E6
in particular manifests a high oncogenic potential
and mediates the degradation of the p53 antioncogenic protein. E7, in turn, has the ability to bind
and degrade another antioncogene, the cellular RB
protein [11, 12].
Products of the late region (L) include two
structural proteins of HPV, L1 and L2. They form
the viral capsid and are synthesized exclusively in
differentiated keratinocytes. The most important of
these proteins is coded in L1 region, while L2 region
codes additional proteins of the viral capsid [3].
The LCR is a significant non-coding fragment
of viral DNA, accounting for about 10% of the entire genome. It performs regulatory functions, affecting the transcription of the E6/E7 genes, which
are particularly involved in the process of neoplastic transformation [13]. The region contains
a promoter sequence (p97), which binds RNAII
polymerase, and binding sequences for all regulatory transcription and replication factors of viral
genetic material. All the LCR regions of HPV that
have been examined so far contain specific enhancers that provide the virus with specific tropism to
stratified squamous epithelial cells [14].
Epidemiology and Risk
Factors in HPV Infection
Human papilloma virus is the most common
sexually transmitted infection, particularly in
young individuals. It is estimated that over 50% of
sexually active women become infected with one
or several HPV types in their lifetimes [15]. The
prevalence of HPV depends on the geographical
region and the prevailing standard of living [16].
Around 20 types of HPV have been found to be
associated with the development of cervical cancer
HPV 16 is identified as being the most oncogenic
type, detected in 53% of cervical cancer followed by
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Role of HPV in Malignant Transformation in Cervix Epithelial Cells
HPV 18, HPV 45, HPV 31 and HPV 33 and HPV
56. Infections with the oncogenic types represent
over 50–75% of all HPV infections [15, 16].
The most significant risk factors in HPV infection include age and sexual activity [17]. Infection is most frequent in women between 20 and 40
years of age, with the peak of incidence between
15 and 25 years of age. As women’s age progressed
the rate of infection decreases, and after age 40 it
remains at a stable low level. In post-menopausal
women HPV infection occurs seldom, but it is always associated with a very high risk of developing cervical cancer [18]. The risk of HPV infection
significantly increases with the number of sexual
partners. Another factor associated with increased
risk of HPV infection is prolonged use of hormonal contraception, due to the effects of estrogens
and progesterone, which stimulate transcription
and cell proliferation and overexpression of E6
and E7 oncogenes [19]. Some investigators also
note an increased risk of HPV infection in women
who smoke cigarettes [20, 21]. Other factors that
increase the risk of HPV infection and cervical
cancer are pregnancy and multiparity. Incidental
or persistent infections with high-risk HPVs are
detected in 30% of pregnant women; however,
the virus is transmitted in the perinatal period in
only 2% of newborn infants whose mothers were
infected with HPV [22, 23].
Persistent infection with a high-risk type of
HPV is the most significant factor in the neoplastic transformation of mucosal cells of the uterine
cervix [15, 19]. In women between 15 and 25 years
of age most infections are transient, and in around
70% of the patients they spontaneously vanish
around one year following the detection of the virus [24]. On the other hand, a protracted infection,
lasting over one year, is associated with infection
with the highly oncogenic virus types, particularly
with HPV 16 [15, 19, 25].
The Mechanism of HPV
Penetration and Infection
Infection with human papilloma virus is usually sexually transmitted. Infection follows microinjuries of the mucosa that uncover the basal layer
of stratified squamous epithelium [26]. This allows
the virus to penetrate to deeper epithelial layers
with epidermal growth factor receptors (EGFRs),
integrins α-6 and also receptors for HPV. The
penetration of viral particles to deeper layers of
the epithelium is followed by an incubation period
lasting from around 3 weeks to 8 months, with
subsequent expression of viral proteins [7]. At
the beginning, the early proteins of the virus are
expressed in the basal and parabasal layers of the
epithelium [11]. Subsequently, the later, structural
proteins of the virus are expressed in the cells of
higher layers. Expression of the late proteins increases as the distance from the surface of mucosal epithelium decreases. At this stage, synthesis
of structural proteins takes place and mature viral
particles are produced [5, 7, 11].
As noted above, chronic infection with a highrisk type of HPV is the most significant factor in the
progression of pathological lesions into cancer of
the uterine cervix [15, 19]. However, only a few of
the infections and lesions induced by the presence
of HPV lead to neoplastic transformation. Most
HPV infections undergo regression within 12–18
weeks after infection. This suggests that a number
other factors (such as immune system imbalances,
treatment with immunosuppressants, coexistent
infections) occurring along with viral particles are
decisive for the neoplastic transformation of epithelial cells in the uterine cervix [19].
The Mechanism of HPV-Induced Neoplastic
Transformation of Cells
The process of cell neoplastic transformation
is complex and multistage. Even if infection with
highly oncogenic types of HPV is decisive for the
process, on its own it is not sufficient to induce
the development of a malignant tumor [7, 27, 28].
Other significant factors include the duration of
the infection, environmental factors, cigarette
smoking and the age and health of the infected
person [24]. The development of a tumor requires
mutations in genes controlling cell division, cell
growth and differentiation [5].
Integration of HPV
with the Genome
of the Host Cell
Particles of HPV are present in cells of the mucosal epithelium of the uterine cervix in episomal
or integrated forms. The episomal form is present
in primarily infected, undifferentiated epithelial
cells, while in tumor lesions the viral DNA is detected in the integrated form with the genome of
the host cells [28].
The process of neoplastic transformation induced by high-risk HPV types (e.g. HPV 16 and
HPV 18) can be initiated only when the viral ge-
238
U. Ciesielska et al.
nome becomes integrated with the DNA of epithelial cells. The E6 and E7 proteins of the high-risk
viruses induce deregulation of the host cell cycle,
prevent apoptosis, promote transition between
G1/S and G2/M phases, promote evasion of cell
cycle checkpoints and activate telomerase activation in the cells [29].
The integration of HPV with the host cell genome leads to disruption of viral DNA in the E1
and/or E2 region, and also to a loss of E2-adjacent
ORFs, i.e. E4, E5 and a part of L2. However, ORFs
E6 and E7 remain intact during the integration
process [30]. Disruption of E2 and/or E1 readout
frames leads to the inhibition of the gene expression [7]. In HPV-induced neoplastic transformation of cells, the loss of correctly functioning E2
regulatory protein is of key importance, since that
protein controls expression of the E6 and E7 genes
through the sequences located in the LCR region.
A lack of repression by the E2 protein results in
overactivation of viral E6 and E7 genes, leading
to synthesis of the two oncogenic proteins [7, 30].
The oncoproteins exhibit the ability to bind and
to degrade anti-oncogenic cell products, p53 and
pRb proteins [28]. In this way, the DNA repair
process is disrupted in the host cells, promoting
their proliferation and growth and delaying their
terminal differentiation [5].
Only early genes undergo expression in the
epithelial basal layer, while the E6 and E7 proteins
are expressed in higher layers of the epithelium,
which stimulates the replication of DNA in the
host cells and allows for replication of viral DNA
[7, 31]. In the initial phase of the infection, most
infected cells in the basal layer of the epithelium
contain HPV DNA in the episomal form (not
integrated with the DNA of the infected cells).
Neoplastic progression is accompanied by the
integration of viral DNA with the cellular DNA.
The presence of the E6 protein promotes the integration of viral DNA with the host cell genome
[9]. The transformed cells contain an insignificant
amount of viral DNA; only the E6 and E7 genes
are expressed, while the late capsid proteins, L1
and L2, cannot be detected [32].
The Effect of the E6 Protein
on the Neoplastic
Transformation of Cells
E6 binds to the tumor-suppressor p53 protein,
leading to its proteolysis by the ubiquitination of
proteasomes [11]. In normal cells p53 manifests
a low level but in response to DNA damage and
viral infections its expression increases. The p53
protein is involved in controlling the cell cycle,
DNA repair and apoptosis [7]. In the presence of
the E6 protein, the activity of p53 becomes suppressed, which may disrupt the cell division cycle,
promoting cell proliferation and increasing the
frequency of spontaneous mutations. This may
consolidate chromosomal instability in cells infected with high-risk types of HPV [5, 7].
In normal cells, the ubiquitin-dependent degradation of p53 involves, among other factors,
Mdm2 ligase [33]. In cells with viral DNA, the
degradation is fully dependent on E6 HPV and develops with the participation of E6AP ligase [34].
The oncoprotein E6 forms a stable complex with
E6AP ligase. The complex binds p53 and leads to
its proteolysis [35].
Effective degradation of p53 depends on the
type of HPV that infected the cell. The efficiency of
p53 protein degradation in various HPV types depends on the ability of the oncoprotein E6 to bind
the p53 protein and E6AP ligase. The E6 protein in
both low- and high-risk mucosal types binds p53,
but it is only in the high-risk types that it effectively
degrades the protein. This reflects the ability of the
E6 protein in high-risk virus types to form a strong
complex with E6AP ligase and to bind a distinct
domain of the p53 protein. Dermal types of HPV,
on the other hand, are completely unable to bind
with E6AP and p53. High-risk viruses vary in their
efficacy in p53 degradation: E6 of HPV 16 binds
the ligase with a higher affinity and the degradation
of p53 is more efficient than that of E6 in HPV 18;
the E6 protein of HPV 11, on the other hand, forms
a very weak association with ligase [36, 37].
Apart from the p53 degradation-dependent
mechanism, HPV has developed several other
mechanisms that prevent programmed cell death.
The various pathways in which the viral E6 protein interacts with the host cell are presented in
Figure 1. In this way the survival and proliferation
of cells with damaged DNA and the accumulation
of mutations in the cellular genome are promoted.
This leads to the neoplastic transformation of host
cells with integrated HPV DNA. The E6 protein of
HPV also prevents apoptosis by degrading factors
other than p53. Bak is one of proapoptotic proteins
that undergoes ubiquitin-dependent proteolysis
when affected by HPV E6/E6AP: A high level of
Bak is found in the upper layers of the epithelium,
but the E6 protein of HPV inhibits Bak-dependent
apoptosis [38]. The Fas-associated death domain
protein (FADD) is another peptide degraded by
HPV E6/E6AP: The peptide binds to the death domain (DD) of the Fas receptor, activating caspase 8
and mobilizing the apoptosis pathway. Procaspase
8 is also degraded, which prevents its conversion
to active caspase 8 [39]. Another pathway through
which the virus prevents programmed epithelial
239
Role of HPV in Malignant Transformation in Cervix Epithelial Cells
Fig. 1. Interactions of E6 in high-risk HPV types leading to neoplastic transformation of host cells – adapted from
Ganguly and Parihar [35]
Ryc. 1. Oddziaływanie E6 HPV wysokiego ryzyka prowadzące do transformacji nowotworowej komórek gospodarza
(wg Ganguly and Parihar [35] zmodyfikowano)
cell death involves elevated expression of the inhibitor of apoptosis-2 protein (IAP-2): HPV E6
activates the transcription factor NF-ĸβ, which induces increased expression of IAP-2 [40].
The E6 proteins of highly oncogenic viruses
may also immortalize host cells by their ability
to prevent shortening of telomere length [41]. In
somatic cells every consecutive division of a cell
results in abbreviated telomeres. Telomere length
reflects the age of the cells. Elevated telomerase activity, which adds additional telomere sequences,
has been documented in human neoplastic cells,
and it has been suggested that this may be of significance in the development of tumors [41]. The
activity of the telomerase enzyme is dependent on
the human telomerase catalytic subunit (hTERT).
The E6 and E6AP proteins of high-risk HPV prevent telomere shortening due to increased expression of the hTERT gene. Moreover, the E6/E6AP
complex induces degradation of NFX1–91 (a recently discovered hTERT repressor) and thus increases expression of the telomerase subunit [42].
Host cell neoplastic transformation is affected
by the highly conservative domain at the C-terminal of the E6 peptide, present exclusively in the E6
of highly oncogenic viruses. This domain contains
the XT/SXV motif, which interacts with proteins
containing the PDZ domain [38]. Proteins with
the PDZ domain are responsible for the adhesion and polarity of cells, as well as for intercel-
lular signalling, and their degradation leads to cell
transformation [35] Proteins with the PDZ domain include (among others) human homologues
of the tumor-suppressor proteins DLg and Scrib,
manifested in Drosophila melanogaster; the postsynaptic protein PSD 95; the multi-PDZ-domain
protein (MUPP1); MAGI-1, -2, -3, which are
proteins forming intercellular junctions; PTPN13
phosphatase; and PATG [35].
Neoplastic cells infected with the virus are able
to avoid the immune response. Overexpression of
the E6 protein leads to the blocking and inactivation of p300/ CBP, which is a co-activator of the
NF-ĸβ transcription factor. The NF-ĸβ transcription factor controls (among other things) promoters of the interleukins IL-6, IL-8 and IRF β [43].
E6 also inactivates the co-activator ADA3, which
stabilizes the p53 protein [44].
The Effect of the E7
Protein on the Neoplastic
Transformation of Cells
The E7 protein interacts with proteins of the
retinoblastoma family, such as pRb and homologous
proteins, p107 and p130. E7 binding to pRb releases
the E2F transcription factor from the pRb complex,
activating the transcription of genes that control cell
240
proliferation this leads to the expression of proteins
engaged in the synthesis of cellular DNA, and the
cell enters the S phase of the cell cycle [45].
Viral E7 may bind other host cell proteins,
causing the cell to enter subsequent phases of
the cell cycle [46]. This is how HPV controls the
proliferation of the infected cells and promotes
oncogenesis. HPV E7 interacts with histone diacetylases (HDAC), a class of enzymes that act as
co-repressors of gene transcription: Their interactions with the E2F transcription factor prevent the
activation of several genes, the products of which
are involved in cell proliferation. The binding of
E2F by viral E7 makes this repression impossible
and promotes transcription of the genes [46].
The E7 protein may also bind to the complex of
cyclin A/CDK2 and cyclin E/CDK2. This activates
kinases, leading to the phosphorylation of pRb and
the transcription of genes involved in cells entering
the S phase of the cell cycle [47, 48]. Another way
in which the virus promotes the amplification of
its genes involves interactions with a group of proteins called CDK inhibitors (CKIs). The HPV E7
protein binds to such proteins as p21 or p27. This
allows the checkpoints that control the progression
of cells from G1 phase to the S phase of the cell
cycle to be bypassed [49, 50].
It has also been found that the E7 protein affects the expression of interleukin 6 (IL-6) and
the pro-apoptotic factor Mcl-1. Overexpression of
IL-6 and Mcl-1 induced by HPV E7 inhibits the
development of apoptosis in cells with integrated
viral DNA [51]. Tumor cells with HPV are able to
avoid the immune response due to the E7 protein
binding with the interferon regulatory factors IRF1
and IRF9, which results in the inactivation of the
factors and blocking of the the interferon α (IFNα)
signalling pathway [52, 53]. Various interactions
of the viral E7 protein are presented in Figure 2.
U. Ciesielska et al.
Vaccines Against HPV
As noted earlier, infection with HPV is the
most common sexually transmitted viral infection
all over the world; and infection with high-risk
types of HPV may lead to carcinoma of the uterine
cervix or other urogenital organs [54]. Viruses of
HPV types 16 and 18 are responsible for around
70% of all cervical cancer cases and for most preneoplastic intraepithelial lesions [25, 55]. Cancer
of the uterine cervix is the second most frequent
malignant tumor in females [25, 31]. Since the
presence of oncogenic HPV types correlates with
the development of neoplastic lesions in the uterine cervix, the application of a prophylactic vaccine
against oncogenic genital types of HPV is the most
effective form of prophylaxis against the development of such tumors [15, 31].
Commonly used prophylactic vaccines against
various viral diseases are directed against infectious agents that induce systemic diseases, rather
than against a local infection such as infection with
papilloma virus. HPVs are viruses that take advantage of cell proliferation in their life cycle but do
not induce cell lysis, which is reflected by the poor
immune response of the host. In contrast to lytic
viruses which are rapidly detected by the immune
system (causing host cell destruction at the terminal stage of infection), antibodies directed against
HPV capsid proteins arise as late as 6–12 months
following the infection [56]. Moreover, in recent
years studies have proved that viruses may develop
mechanisms shielding them from the immune system or slowing down its reaction [28, 56].
Despite such limitations, recent research has
resulted in the production of a vaccine which is
100% effective in preventing the development of
precancerous lesions, non-invasive carcinoma of
the uterine cervix and pointed condylomas, which
Fig. 2. Interactions of E6 in high-risk HPV types leading to neoplastic transformation of host cells – adapted from
Ganguly and Parihar [35]
Ryc. 2. Oddziaływanie E7 HPV wysokiego ryzyka prowadzące do transformacji nowotworowej komórek gospodarza
(wg Ganguly and Parihar [35] zmodyfikowano)
Role of HPV in Malignant Transformation in Cervix Epithelial Cells
are linked to infection with HPV types 6, 11, 16
and 18 [19, 57]. The development of the vaccine
was advanced by the studies of Professor Harald
zur Hauser, who was awarded the 2008 Nobel
prize in medical sciences. Production of the prophylactic anti-HPV vaccine was announced by two
pharmaceutical companies [1, 24]. These proved
to be virus-like vaccines, consisting of the paraviral protein L1 (a virus-like particle – VLP), which
represents the principal viral capsid protein. The
vaccines contain no viral DNA and therefore have
no ability to infect cells, to stimulate proliferation
or to induce pathological lesions [31]. Similarly to
the course of natural infection, VLPs induce antibody production [31, 58]. In a natural infection
the antibodies are directed against epitopes of the
L1 capsid protein of HPV. The L1 and L2 proteins
of HPV manifest the ability to self-assemble and
to form virus-like particles of viral capsid [31, 54].
Large quantities of HPV L1 protein can be obtained using genetic engineering techniques: The
HPV L1-coding gene is introduced to plasmid vectors or recombined baculoviruses. Subsequently, it
undergoes translation to L1 protein in yeast cells
or insect cells cultured in vitro. Following export
from the cells, L1 protein particles self-assemble
into VLPs [59]. The VLPs obtained closely resemble the structure of native HPV virions and they
induce the production of neutralizing antibodies
[56]. Since they do not contain viral DNA, they
are not infectious and have no oncogenic potential to induce neoplastic transformation of cells in
the vaccinated individual. The viral-like particles
of genital HPV types are highly immunogenic and
application of even small doses of L1 VLP results
in the production of large numbers of antibodies
against the protein [58]. The vaccination results
mainly in the production of IgG1 class antibodies,
which effectively neutralize HPV particles [60].
Currently, two vaccines against HPV are available on the market. The bivalent vaccine is directed against HPV types 16 and 18, while the tetravalent vaccine is targeted at the four so-called genital
types: HPV 16, HPV 18, HPV 6 and HPV 11. The
efficiency of the tetravalent vaccine was proven in
the clinical trials FUTURE I and FUTURE II, conducted all over the world [57, 61, 62]. Over 12,000
women from 13 countries (including Poland) took
part in the latter trial. The participants were from
241
16 to 23 years of age and received three intramuscular doses of the tetravalent vaccine or placebo
[62]. In every case gynecological and cytological
examinations were conducted both before vaccination and on a few occasions following vaccination. Clinical examinations and observations conducted in the study’s second phase (which lasted
5 years) and third phase (which lasted 2–2.5 years)
demonstrated the tetravalent HPV vaccine’s 100%
effectiveness in the prevention of uterine cervix
carcinoma, cervical intraepithelial neoplasias types
CIN2/3 and preneoplastic lesions of the vulva and
vagina [57, 63]. However, the vaccine manifests
no therapeutic activity: It cannot be used to treat
already existing genital warts or developing carcinoma of the uterine cervix [25]. Tests continue
on vaccines that might offer treatment of diseases
induced by HPV infection [18, 31], but the results
of preliminary studies are not promising. This is
explained by the fact that during long-term infections linked to the presence of viral DNA in
epithelial cells, no expression of L1 protein occurs
[31]. In experimental studies conducted on animals with pathological lesions in the epithelium,
the administration of VLP induced no therapeutic
effects even if it provided protection when applied
prophylactically [26]. Thus, administration of an
HPV vaccine is justified to prevent infection. According to a statement by Polish Gynecological Society experts, vaccinations against HPV should be
administered to girls at the age of 12 to13, before
the start of their sexual activity and before their
bodies have contact with HPV [64]. The vaccine
may also be effective in women who have started
sexual activity but have had no contact with HPV.
The effects of chronic HPV infection, with
sequels linked to treatment and medical expenditures, as well as the psychological aspect of uterine
cervix carcinoma, represent a very serious social
problem. There is therefore a real need for routine
administration of the vaccine to women, particularly in countries with very irregular or no screening examinations. Widespread application of
anti-HPV vaccines might significantly reduce the
incidence of uterine cervix carcinoma. Whether or
not the vaccine will be widely used and promoted,
the key problem remains: making women aware of
the need to conduct regular cytological monitoring examinations [9].
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Address for correspondence:
Urszula Ciesielska
Department of Histology and Embryology
Wroclaw Medical University
Chałubińskiego 6a
50-68 Wrocław
Poland
Tel.: +48 71 784 13 55
E-mail: [email protected]
Conflict of interest: None declared
Received: 3.06.2011
Revised: 4.11.2011
Accepted: 29.03.2012