Human papillomavirus pathophysiology
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Human papilloma virus is usually transmitted via the sexual route to the human host. HPV life cycle is linked to epithelial differentiation and maturation of host keratinocytes, with transcription of specific gene products at every level. The pathogenesis of HPV infection causing cancer is mainly linked to high risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). E6 and E7 protein products of HPV interact with two important cell cycle regulatory protiens, P53 and Rb proteins of host cell, causing unchecked cellular replication accumulating mutations leading to cancer.
- Human papilloma virus is usually transmitted via the sexual route to the human host.
- Different types of HPV has a predilection for different types of epithelial tissue.
HPV life cycle
- HPV life cycle is linked to epithelial differentiation and maturation of host keratinocytes, with transcription of specific gene products at every level.
- HPV primarily infects basal cell layer of stratified squamous keratinised epithelium.
- Following transmission, the HPV uses the microabrasions to enter the basal stem cells via tissue specific heparan sulfate proteoglycans through clathrin-mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV.
- It than undergoes viral uncoating and viral DNA genome is than transported to nucleus maintaining a low copy number 10-200 viral genomes per cell (episome form).
- A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium.
- HPV uses host DNA replicative machinery to multiply as it lacks DNA polymerase activity.
- Specific viral genes are transcribed at every level of keratinocyte differention.
- Early proteins: E1, E2, E3, E4, E5, E6 and E7 proteins are synthesized primarily in middle layers, for reactivation of replication process in the differentiated cells.
- Late proteins: L1, L2 proteins are transcribed in the most superficial layers for virion assesmbly, release and reinfection, as they code for capsid proteins.
Pathogenesis of HPV induced cancers
The pathogenesis of HPV infection causing cancer is mainly linked to high risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). Following HPV proteins play a significant role in the development of cancers associated with HPV.
E6 and E7 proteins
E6 and E7 protein products of HPV interact with two important cell cycle regulatory protiens, P53 and Rb proteins of host cell, causing unchecked cellular replication accumulating mutations leading to cancer.
- Inhibition of P53
- P53 protein is a cellular check point at G0/G1 to S phase of cell cycle and is also responsible for cell apoptosis for unrepaired DNA mutations. E6 protein binds P53 which results in degradation of P53, leaving cell without any check for mutations and unregulated cell.
- Inhibition of Rb protein
- Rb protein is negative regulator of cell growth. It binds E2F transcription factor which controls DNA replication and cyclin protein induced entering of cell into S phase of cell cycle. E7 protein binds Rb/E2F, releasing E2F from the inhibitory effect of Rb causing increased cyclin induced entry of cell into S phase of cell cycle, resulting in increased replication rate of cells accumulating mutations.
|Common warts||2, 7|
|Plantar warts||1, 2, 4|
|Flat cutaneous warts||3, 10|
|Anogenital warts||6, 11, 42, 43, 44, 55 and others|
|Genital malignancies||16, 18, 31, 33, 35, 39, 45, 51|
|Epidermodysplasia verruciformis||more than 15 types|
|Focal epithelial hyperplasia (oral)||13, 32|
|Oral papillomas||6, 7, 11, 16, 32|
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