1
The Cell: Basic Structure and Function
Disruption of
cell growth cycle
Regulation of
virus gene expression
and virus replication
Membrane
signaling protein
Assembly
Gene
and release
expression
Fig. 1.12 Human papillomaviruses.
Top: electron microscopy pictures of
viral particles and viral DNA. Bottom: Schematic diagram of the viral genome
indicating the most viral genes and most important functions.
Papillomaviruses infect the basal cells of the epithelium via
binding to certain cell-surface glycosaminoglycans expressed
on the basal cells of the epithelium (Fig. 1.14) . Once they have
entered the cell, the viral capsids are broken down and the
episomal viral genome is released in the nucleus. Viral early
genes are expressed at this stage on a very low and highly con-
trolled level that allows for low copy replication of the genomes
on the order of 10 to 50 genomes per infected basal cell; how-
ever, massive amplification of the viral genome or even repli-
cation of the virus does not occur at this stage of infection in
basal cells. Only in certain instances not yet characterized in
detail does high-level gene expression of the viral early genes
occur in differentiated cells of the intermediate layers of the epi-
thelium. This triggers amplification of the viral genome. Once
the cells have reached the superficial cell layers the early genes
are shut off and high-level expression of the late genes (L1 and
L2) occurs (early-late switch). This results in expression of the
Table 1.1
Correlation between phylogenetic and epidemiologic
classification of mucosal HPV types
Phylogenetic
classification
Epidemiologic classification
High-risk HPV types
Low-risk HPV types
High-risk HPV
types
16, 18, 31,33, 35, 39, 45,
51,52, 56, 58, 68, 82,
26
*,
53
*,
66
*
70
Low-risk HPV
types
73
6, 11,40, 42, 43, 44, 61,
72, 81, CP6108
* P u t a t iv e h ig h ris k t y p e s .
T h e e p id e m io lo g ic a l c la s s ific a t io n o f t h e s e t y p e s a s p r o b a b le h ig h ris k is b a s e d o n
z e r o c o n t r o ls a n d o n e t o t h r e e p o s it iv e c a s e s .21
respective proteins, packaging, and self-assembly of new mature
viral particles that are finally released from the cells once dur-
ing the normal differentiation process the infected and virus-
producing keratinocytes decay into keratin fragments. The
replication strategy of the human papillomaviruses is therefore
tightly linked to natural differentiation processes of their host
cells. For the virus this has two advantages.
First, the biology of the primary host cells at the bottom of
the epithelium that retain the capacity to multiply and gener-
ate new cells is only marginally altered by the infection. HPV
infections induce no cytolysis, no inflammation, or other tissue
damage in the basal cell compartment of the epithelium. Acute
LR-HPVs induce more proliferation of the infected basal cells
and cause exophytic lesions that may clinically impress as warts
or condylomata seen with comparable incidence in men and
women. Proliferation of basal cells is induced by acute HR-HPV
types to much less extent since a simple infection almost never
causes exophytic lesions. Usually these infections regress spon-
taneously and clinically unrecognized.
Secondly, due to the fact that the virus is only produced on
the very superficial surfaces of the infected epithelium there is
very limited contact between viral antigens and the immune sys-
tem of the infected host. Thus the acute infection induces very
little humoral immune responses and serum antibodies are only
observed in low titers in some of the infected individuals. They
do not induce a protective humoral immunity. Cellular immune
responses are only weakly activated, which usually takes a long
time during which the virus can multiply and spread until reli-
able cytotoxic immune functions have been activated to defeat
the virus and the lesions it has caused.
The tight association of the replication strategy of the papillo-
maviruses with the differentiation status of their host cells further
allows the virus to multiply and spread with a highly restricted
amount of their own genetic information. Complex genetic fea-
tures that control the restricted expression pattern of the virus dur-
ing the different differentiation stages are contributed apparently
by the host cell and not by the virus; thus the virus has no need to
retain genes that may mediate these functions by themselves.
Epidemiology of HPV Infections
HR- and LR-HPV infections are usually acquired in the early
years upon uptake of sexual activity. Most studies have been
performed in women, but it can be extrapolated that the
17
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