General Cytology
1 to 6 months
First lesion
Fig. 1.13 Different types of HPV infection.
(1) A state of very low viral activity shortly after initial infection through microlesions of the epithelium
("latent phase"). (2) The replicative infection characterized by strong viral gene expression and viral capsid formation in the upper differentiated epithelial
layers. (3) The transforming infection characterized by deregulated oncogene expression in the replication competent basal cells. CIN, cervical intraepithelial
neoplasia, grade 1-3.
infection pattern in men is not substantially different from that
in young women. The highest infection rates are seen in young
women at 18 to 25 years of age.22 Over time the incidence of
HPV infections decreases, but there seems to be a second peak
of HPV infections in older women of more than 45 years of age.
The infection clearly shows a typical sexually transmitted pat-
tern and depends on personal lifestyle habits, for example, the
number of sexual partners, and the frequency of sexual contact
with partners who have themselves sexual contact with other
partners. Several studies have shown that the cross-sectional
incidence of HR-HPV infections ranges between 3 and 25%
of the female population. The cumulative infection in average
women is calculated to be more than 50% once in their lifetime.
Thus a tremendous amount of women (and hence also men) are
infected with these agents.
The HPV types 16 and 18 are found in about 70% of all
cervical carcinomas, whereas among healthy women the
remaining HR-HPV types are more common. This observa-
tion suggests that women infected with the two types, HPV
16 and 18, may have a higher risk to developing high-grade
precursor lesions or even invasive carcinomas than women
who are infected with the other HR-HPV types.23 This notion
is strongly supported by a variety of studies that indicate
that women infected with HPV 16 and 18 are more likely to
develop high-grade lesions (cervical intraepithelial neoplasia
(CIN) 3) in less time than women infected with other HR-
HPV types. Moreover, the time of progression of high-grade
lesions to invasive carcinomas appears also to depend on
the HPV type that causes the high-grade lesions.23a
HR-HPV infections usually last for several months and in
most instances regress spontaneously without causing relevant
clinical lesions.24 The acute HPV infection may impress as CIN
1 lesions in histological sections in that the typical koilocytes
indicate the acute replication of the virus in intermediate and
superficial cells of the infected epithelium. These acute infec-
tions strictly adhere to the regulatory gene expression pat-
tern outlined earlier in that the cellular differentiation stage
determines the expression of the viral genes in the epithelium.
According to this, limited and highly regulated gene expression
is found in basal and parabasal cells of the epithelium. By this
replication strategy, HPVs successfully avoid expression of
viral genes in proliferation competent epithelial cells that may
become transformed stem cells for a cancer. Under "normal"
conditions viral genes are only expressed in cells that are irre-
versibly cell cycle arrested. HPVs thereby can multiply almost
unnoticed by the host and spread to many other individuals
(Fig. 1.14).
The Role of the HR-HPV E6 and E7 Genes
The causal relationship of HR-HPV types and cervical cancer is
based on four major experimental observations:
1. In more than 99% of cervical cancers genomes of
HR-HPV types can be found;
2. Two viral genes, E6 and 7, are in all cervical cancer
preserved and expressed;
3. The E6 and E7 genes can transform primary epithelial
cells into neoplastic cell clones; and
4. If the expression of these genes is inhibited cervical
cancer cells stop to proliferate and lose the neoplastic
growth properties.
These facts clearly underline the central role of the viral
E6 and E7 genes for the HR-HPV mediated transformation
During the past 20 years basic research on the biochemical
activities of both viral proteins have revealed three major aspects
that underline their oncogenic activities: the E6 protein of the
oncogenic HPV types induces premature degradation of the p53
tumor suppressor gene and thus interfere with its proapoptotic
functions25; the E7 protein induces destabilization of the retino-
blastoma protein complex and thus allows the cell to evade cell
cycle control at the G1/S phase transition thorough the pRB
pathway26; and both genes interfere with centrosome synthesis
and function that results in desegregation of the chromosomes
during mitosis and numerical and structural chromosomal
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