Hpv Lifecycle In Cervical Cancer

HPV infection of the genital tract is a very common sexually transmitted disease being prevalent in women under and above 25 years, obviously, linked to multiple sexual partners. Infection is usually asymptomatic . Most cervical cancer arise in the cervical transformation zone, an area with squamous metaplasia between the proximal squamous epithelia found at the border with ectocervix and vagina and the columnar epithelia in the endocervix ( Ramanakumar A.V., et al. 2010). Cervical cancer is thought to develop through a continuum of progressive cellular changes from mild to moderate CIN II to severe carcinoma in situ spreading over a period of 1 to 4 years. HPV life cycle is tightly linked to the differentiation of its host epithelial cells, infecting the squamous epithelium in three stages: a) establishment, b)maintenance and c) amplification where the basal epithelial cell layer are mitotically active , serving for its replication, penetrating through small wounds. Basal-like cells at the cervical squamo -columnar junction are particularly susceptible and accessible to HPV infection . Hence, HPVs infect immature, undifferentiated proliferating cells and cannot infect the mature superficial squamous cells that covers the ectocervix ( Coleman W.B., et al. 2009 )Basal cells are not readily accessible for viral infection as they are protected by several layers of differentiated cells that have withdrawn for the cell division cycle. These cell layers are essential for the mechanical stability of the skin and shields the proliferating basal cells from environmental genotoxic insults (Pyeon M., et al. 2009 ).

The best understood mechanism by HPV infection is in the cervical cancer as HPV taking advantage of the differentiation pathway of keratinocytes and the fact that the cells die naturally with subsequent detachment, a process known as anoikis associated with virion release. After entering nucleus viral DNA is rapidly amplified concomitantly with the host DAN. A very interesting feature of HPV is to maintain its viral genome as extra-chromosomal DNA in the nuclei of infected cells for a long period of time certifying that all the viral DNA is successfully inherited to each daughter cells during cell proliferation and this is mediated by the early proteins (Pittayakhanjonwut D. 2010). Human papillomavirus is organised by eight genes E1, E2, E4, E5, E6, E7 referred to as early genes and L1 and L2,the late genes that are expressed at different times during HPV life cycle. Co-existence of integrated and episome HPV will result in replication amplification of episomal DNA by E1 and E2 of integrated HPV associated with chromosomal abnormalities and re-replication of integrated viral DNA linked to activation of DNA repair and recombination system resulting in acquiring of mutations ( Pirot C.E., et al. 2011) . As the keratinocyte differentiates, other early HPV gene expressed are E4 and E5 play a role in modulating the productive phase of HPV life cycle and control the rate of epidermal growth factor, whereas E6 and E7 modulate cell cycle control and contribute to viral genome maintenance ( Kajitani N., et al. 2012) Finally during the terminal differentiation of the keratinocyte in the stratum corneum late viral protein expression (L1, L2) and virus assembly occurs. L1 undergoes structural changes to expose L2 and the viral genome by an uncertain process: melting or disulphide bonds. Late genes expression is limited to the uppermost layer of epithelium. Thereafter, following the natural desquamation process where the outermost layer of epithelial cells are shed, virus is shed at the same time. In vitro studies with monolayer cell culture showed HPV infection, for that reason it remains unclear why this differentiation of cell layers is necessary so that HPV infection to occur (Lambert P.F 2005) .