Biology Reference
In-Depth Information
acts as a transcriptional regulator both activating and tightly limiting the expres-
sion of the viral genes E6 and E7 during the early phase of virus infection
(Longworth and Laimins
2004
). During this stage of the HPV life cycle, the HPV
genome is maintained as a circular episome at low copy number, approximately
50-100 extrachromosomal copies per infected cell (Stubenrauch and Laimins
1999
). The HPV genome can persist for years, even decades, in the nuclei of these
infected cells in a non-productive state (McLaughlin-Drubin and Munger
2009
).
The E4 and E5 proteins play a less well-understood role in the viral life cycle. The
E4 protein may play a role in virus egress from the cell by inducing the collapse of
the cytokeratin network (Doorbar et al.
1991
). The E5 protein is necessary for
optimal growth of the virus, possibly involving interaction with the epidermal
growth factor receptor (EGFR) (Pim et al.
1992
; Straight et al.
1993
).
Normally, as progeny cells of the basal epithelium layer migrate toward the
upper stratum they undergo terminal differentiation and exit from the cell division
cycle. Exit from the cell division cycle is adverse to the productive phase of the
HPV life cycle. This is because HPV does not encode any of its own replicative
enzymes and is entirely dependent on host cell DNA replication machinery to
amplify the viral genome. In order to keep infected host cells in a replication
competent state as they migrate to the epithelial surface, the high-risk HPV
genome encodes two oncoproteins, E6 and E7, which disrupt host cell cycle
control, preventing exit from the cell division cycle and promoting activation or
re-expression of cellular replication factors necessary for viral replication (Hebner
and Laimins
2006
). Viral genome amplification and productive HPV infection is
tightly regulated and only occurs in differentiated cells located within the supra-
basal epithelium layer (Longworth and Laimins
2004
). Differentiation-dependent
expression of viral capsid proteins in these cells promotes the assembly of
infectious virions. Eventually, infected desquamated cells are shed off the upper
epithelial layer, promoting spread of viral progeny.
12.4 Function of High-Risk HPV Oncoproteins
High-risk HPVs express two oncoproteins, E6 and E7, which function to dereg-
ulate the host cell cycle in order to promote amplification of the viral genome.
Long-term expression of HPV E6 and E7 oncoproteins are known to both extend
the life span of primary human cells and facilitate their immortalization whereas
transformation is rare (Munger et al.
1989
).
Despite the high prevalence of HPV infection in sexually active women, most
HPV infections are self-limiting and transient. However, rarely and several years
or even decades after infection with high-risk HPV types, SCCs may form.
Carcinomas develop following integration of the high-risk HPV genome into host
chromosomes (Baker et al.
1987
). Integration of the viral genome terminates the
productive life cycle of the virus. Viral genome integration can occur throughout
