Papillomaviruses Flashcards
What are the origins of Papilloma viruses thought to be?
- changes in the epithelium of reptiles millions of years ago
- coexisted with their hosts for along time so co-evolved, explaining why they often cause no or very mild symptoms (warts)
Which genera of papilloma virus infects humans?
- alpha papilloma virus
- akak human papillomavirus HPV
Describe the HPV virion
- small and non-enveloped
- has a capsid built from 72 pentameric capsomer subunits which is more resistant to destruction than an envelope
Describe the structure of the HPV genome
- contains a long control region (LCR)
- 8 genes spliced into a larger number of gene products
- 6 early (E) genes and 2 late (L) genes
- size and position of the major ORFs differs between HPV strains
What are the roles of HPV early genes E1 and E2?
viral DNA replication alongside host DNA replicationW
What are the roles of HPV early genes E3 and E8?
these are putative genes seen only in some HPV strains
What are the roles fo HPV early genes 4 + 5?
neede for amplification of the viral genome in the upper layers of the host epithelium
What are the roles of HPV early genes E6 and E7?
are oncogenic in high-risk HPVs - immortalise and genomically stabilise cells
What are the roles of HPV late genes L1 + L2?
form the viral capsid when in the upper host epithelium
What is the role of HPV LCR?
contains regulatory sequences needed for viral genome replication and expression
How does HPV replicate in host cell?
- attachment and entry (basal epithelium)
- uncoating and genome entry (circular dsDNA)
- replication and transcription (by host machinery)
- late gene expression and capsid formation
- assembly and release (cell lysis)
- infection of adjacent cells
How do HPV cells enter the epithelium and how is it maintained/regulated there?
- micro-wounds/lesions allow cells to acess the basal lamina and infect
- can be maintained in low copy number episomes in these less differentiated cells
- as the cells move upwards and begin to differentiate the virus begins to replicate and express late genes to produce new HPV virions in terminally differentiated cells
How can HPV persistently infect epithelial cells?
- at the basal lamina
- increased E6 and E7 expression
- can cause the formation of pre-cancerous lesions
- viral load is highest at this precancerous state
What kind of epithelial cells can HPV infect?
infect squamous epithelial both cutaneous and mucosal. infection of mucosal epithelium can be more invasive and dangerous
Which HPVs are associated with which outcomes?
- 30 HPVs associated with genital warts and growths
- 15 associated with cervical cancer
- HPV-18, 16 and 33 make up 70% of this
How is HPV transmitted?
- sexual contact
- mostly sexual intercourse
What is the significance of HPV-16 and HPV-18 in cervical cancer?
- the only HPVs that can give rise to immortalised cell lines
- co-operate with ras oncogenes
- HPV association with cancer is stronger than that of smoking
Where is HPV most common?
- in low-middle-income countries with less education and vaccination
Give some stats on cervical cancer (2)
- 52% mortality
- 7% of women with HPV-16 will develop cervical cancer within 45 years of infection
Name 3 risk factors/ cofactors for cervical cancer
- smoking
- age at first intercourse
- number of sexual partners
What are the major steps of cervical cancer development?
What features of HPV allow for presistent infection?
- E5, E6 and E7 have roles in immune evasion
- viral gene expression is shut off in the presence of infiltrating lymphocytes but viral episomes are not effectively cleared from the basal cell layer
How does HPV genome DNA integration lead to cancer?
- integration into the genome carries a risk in itself as it can cause genomic instability
- HPV integration specifically can interrupt E2 expression and reduce downregulation of oncoproteins E6 and E7
What cellular processes can HPV E6+E7 interfere with to cause cancer?
- E6 interferes with p53 and activates telomerase
- E7 maintains telomeres and modulates cell cycle progressionH
How does HPV E6 interfere with p53?
- associates with E6qp and causes the degradation of p53 allowing the cell cycle to progress even with incorrect DNA or cell damage
How does HPV E7 modulate cell cycle progression?
- targets Rb for degradation or sequesters it
- E2F is free to bind to the DNA allow passage through the cell cycle
How do HPV E6+E7 activate and maintain telomeres in cervical cancer?
- E6 activates telomerase reverse transcriptase (TERT)
- E7 maintains telomere length through the alternative pathway
- E7 is more important in early cancer and E6 in later cancers
What is the key difference between E6+E7 in high risk and low risk HPVs?
- in low risk is induces cell entry
- in high risk it induces cell entry and immortalisation of cells and can bind to and interact with p53 and Rb
How do we know that immunity plays a key role in the regression of HPV?
- warts more common in those under immunosuppression and can regress when suppression is lifted
- precancerous lesions are much more common in AIDs patients
- antibodies to the L1 protein are seen in those with genital warts
What are HPV L1 vaccines?
- destroy the L1 outer capsid and prevents the virus from entering the cells in the first place
- in clinical trials
- shown sucesses in musocal dog papillomavirus
What vaccine against HPV does exist? Has it worked?
- Gardasil given to girls 9-12
- 90% reduction in HPV infection of targetted strains
- 85% reduction in high-grade abnormalities
- beginning to vaccinate boys to further reduce the spread
What are some important factors to consider when designing new HPV vaccines?
- protective against multiple strains
- protects against other HPV-associated cancers
- duration or level of cancer protection
- accessible and affordable to lower-income countries where 80% of disease burden lays
