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such as HPV-1 and HPV-2, typically promotes the formation of benign lesions
which do not undergo malignant progression, such as skin and plantar warts. An
exception to this are patients suffering from epidermodysplasia verruciformis
(EV), a rare inherited autosomal recessive genetic disorder, which predisposes
patients to the formation of cutaneous SCCs following infection with certain HPV
types, such as HPV-5 and HPV-8 (Berkhout et al. 2000 ;Orth 1986 ).
Mucosal HPVs are further subdivided into two categories: low-risk and high-
risk (de Villiers et al. 2004 ). Low-risk HPVs, such as HPV-6 and HPV-11, are
associated with benign lesions of the oropharyngeal and anogenital tracts such as
oral and laryngeal papillomas and anogenital mucosal condylomata acuminata
(Schiller and Lowy 2006 ). High-risk HPVs such as HPV-16, -18, -31, -33, and -45
are associated with malignant progression and the development of SCCs. Epide-
miological and biological studies have shown that HPV-16 and -18 are the most
oncogenic types within the high-risk group accounting for 50 % and 20 %,
respectively, of cervical cancers (Munoz et al. 2003 ). HPV-16 is also the most
commonly found type in HPV-positive head and neck SCCs (Paz et al. 1997 ).
12.3 HPV Genome Organization and Life Cycle
Oncogenic HPV genomes contain eight open reading frames (ORFs), which are
expressed as polycistronic mRNAs in a temporal manner under control of the
non-coding long control region (LCR) (Longworth and Laimins 2004 ). The LCR
contains the viral origin of DNA replication and important transcriptional control
elements recognized by both cellular and virally encoded regulatory proteins. HPV
early (E) transcripts control viral gene transcription and deregulate host targets to
allow amplification of the viral genome in terminally growth-arrested cells. Early
transcripts of high-risk HPV-16 are under control of a promoter, P 97 , contained
within the LCR (Longworth and Laimins 2004 ). HPV late (L) transcripts, L1 and
L2, encode for the major and minor viral capsid proteins, respectively. Late
transcripts of high-risk HPV-16 are under control of the late promoter P 670 ,
residing within the E7 coding region, which only becomes active in terminally
differentiating keratinocytes (Grassmann et al. 1996 ).
The HPV life cycle is intimately linked to the differentiation state of the
infected host cell (Longworth and Laimins 2004 ). HPV infection is promoted by
microabrasions that occur in the stratified squamous epithelial lining of the skin,
anogenital, and oropharyngeal tracts. These microabrasions allow the virus to
obtain access to cells within the basal, or basement, layer that supports the strat-
ified epithelium. The basal layers contain stem cells that give rise to transiently
amplifying cells, which represent the majority of cells within the cervical
epithelium capable of cell division (Longworth and Laimins 2004 ). Upon infection
of these cells, E1 and E2 viral gene expression is activated. The E1 protein
functions as a DNA helicase and interacts with the E2 protein to bind to the viral
origin of replication (Yang et al. 1993 ; Sedman and Stenlund 1995 , 1998 ). E2 also
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