L2 - HPV

• Human Papilloma Virus (HPV)


  A group of small DNA viruses that induce warts in a variety of higher vertebrates including humans

  
• Papillomaviruses


  • Origin appears linked to changes in the epithelium of first reptiles (around 350 million years ago)
  • Typically cause no or mild symptoms, can however lead to serious disease (cancer)
  • 1933 cottontail rabbit papillomatosis was described – this was the first time a virus had been associated with cancers in animals
  • HPV-16 and 18 (human papillomaviruses-16 and 18) are linked to cervical cancer

  
• Five main Papillomavirus genera

  • Based on alignment of the E1, E2, L1, and L2 genes

  
• HPV virion structure


  The virions are 55nm in diameter. The particles are non-enveloped and are built from 72 pentameric capsomer subunits
• HPV genome


  Typically comprises a long control region (LCR) and eight genes that are necessary for different stages of the virus life cycle. These genes encode a larger number of gene products as a result of mRNA splicing. Six early (E) and two late (L) genes

  
• HPV Genome and Proteins

  • E1 and E2: Required for viral DNA replication
  • E4 and E5: Needed for amplification of the viral genome in the upper layers of the epithelium
  • E6 and E7: Oncogenic, cooperate to immortalize cells and also induce genomic instability
  • L1 and L2: Form the viral capsid, expressed late in infection
  • LCR: Contains regulatory DNA sequences needed for replication and gene expression
  • E3 and E8: Putative genes in only a few papillomaviruses

  
• HPV replication


  1. Attachment and Entry

  2. Uncoating and Genome Entry

  3. Replication and Transcription

  4. Late Gene Expression and Capsid Formation

  5. Assembly and Release

  6. Infection of Adjacent Cells

  
• HPV expression relies on host cell environment. A productive cycle cannot happen unless the epithelial cell is terminally differentiated

  
• Over 200 different types of HPV
• About 30 HPVs associated with genital warts/growths
• About 15 HPVs associated with cervical cancer (although 3 types, 16,18 and 33, account for 75%)

  
• HPV Transmission


  • Transmission by sexual contact, including sexual intercourse and other types of sexual contact (transmission less common)
  • Transmission determined by per partner transmission probability, infectiousness, and average number of partnerships formed per unit time
  • Little reliable epidemiologic data on HPV transmission probability per sex-act or partnership
• All HPVs are capable of inducing transient proliferation, but only HPV 16 and 18 give rise to immortalised cell lines
• HPV 16 and 18 cannot transform primary rat cells alone but they can co-operate with the "activated" ras oncogene to transform these cells
• HPVs are important co-factors in the development of human cancers and preventing HPV infection will have an important impact on human welfare throughout the world

  
• HPV association with cervical cancer is stronger than that for cigarette smoking and lung cancer

  
• Cofactors for cervical cancer

  • Smoking
  • Age at first intercourse
  • Number of sexual partners

  
• 604,000 cases of cervical cancer annually in the world (WHO 2020)

  
• 342,000 deaths from cervical cancer (WHO 2020)

  
• Overall, mortality to incidence ratio of cervical cancer is 52%

  
• Cervical cancer is the third most common cancer in females in the world
• About 90% of the global burden of cervical cancer occurs in low- and middle-income countries (WHO, 2020)

  
• HPV 16/18 infection imparts a 10 - 40 fold increased risk of cervical cancer and are responsible for nearly 50% of high-grade cervical pre-cancers

  
• There is a 20 - 40 years latent period between HPV infection and cervical cancer

  
• HPV is present in 33% of normal young women
• HPV is present in 3% of women over 50 years old
• 1/300 of women with HPV will have low grade CIN (Cervical Intraepithelial Neoplasia)
• 7% of women with HPV16 will develop cervical cancer within 45 years from infection

  
• Several HPV proteins (E5, E6 and E7) have roles in immune evasion as well as in cell cycle entry, which contributes to the ability of HPV to establish persistent infections

  
• Risk of cervical cancer and are responsible for nearly 50% of high-grade cervical pre-cancers

  
• 20 - 40 years latent period
• HPV present in 3% women over 50 years old
• 1/300 of these will have low grade CIN (Cervical Intraepithelial Neoplasia)
• Cofactors likely to be

  • Smoking
  • Age at first intercourse
  • Number of sexual partners
• CIN3


  Cervical intraepithelial neoplasia grade 3
• HPV and cervical carcinoma statistics

  
• Major steps in the development of cervical cancer

  • HPV and cancer
  • Immune regression, latency and reactivation
  • Viral DNA integration
  • Persistent infection

  
• Mechanisms of HPV-induced oncogenesis

  • High risk HPV E6 interferes with p53 cell cycle regulation
  • High risk HPV E6 activates telomerase
  • High risk HPV E7 modulates cell cycle progression
  • High risk HPV E7 promotes telomer maintenance
• The sequences present on mRNA derived from an episomal genome contribute to mRNA instability and help regulate gene expression. When the genome integrates these regions are replaced with cellular sequences and these contribute to abnormal mRNA stability and thus protein expression.
• Viral infection

  DNA damage

  Cell stress

  P53 (high levels)