Viruses and Cancer Flashcards

Question

How has the HPV virus evolved and what is the effect of this evolution

Answer 1

- low level (once or twice) and not express many of its genes – only E6 & E7. - amplifies viral genome in the upper layers of skin because those areas are not under tight immune regulation anymore - This allow it to hide from immune system for decades. - It is only once the infected cells move up through epithelium that the viral genome is amplified up to 1000 copies per cell and the capsid proteins are synthesised. - I.e. infectious particles are only present in upper layers of skin – so virus can hide from immune system

Answer 2

- HPV Infects basal cells (mitotically active) - HPV uses the host cell DNA replication machinery to replicate. - BUT productive replication (where viral DNA is amplified) occurs in cells that would normally be mitotically inactive. - uses oncogenes E6 + E7 to make them enter cycle again - So the virus pushes these cells back into the cell cycle to complete its life cycle

Answer 3

- Retinoblastoma - P53

Answer 4

- E6 & E7 drive cell cycle proliferation to allow the virus to copy its own genome. - They target 2 very important tumour suppressor genes present in the host cell.

Answer 5

- E7 binds and inactivates the tumour suppressor gene retinoblastoma and that pushes the cells to proliferate. - Retinoblastoma → important in preventing cell cycle entry. - Because E7 gets rid of it – these cells now proliferate more rapidly. - normally result in a lot of stress in the cells → activates the tumour suppressor gene P53 which would induce apoptosis in those cells. But this doesn’t happen.

Answer 6

- binds and degrades P53. - So now these cells are being pushed to divide more rapidly as then they should be as - E7 inactivates checkpoint protein RB and P53 is no longer activated as E6 has got rid of it.

Answer 7

- = protein important for a checkpoint or restriction point in the cell cycle going from G1 to S phase. - RB normally phosphorylated or hypophosphorylated

Answer 8

- several positive growth signals can activate cyclin D CDK4,6 complex. - This then phosphorylates Rb - This prevents Rb binding to a family of transcription factors called E2Fs, releasing them to activate transcription of specific genes. - It is E2F TF that drive cell cycle entry. They go into he nucleus of the cell and activate expression of genes important for cell cycle progression - Active E2F enhances transcription of genes required for S phase progression. - RB keeps this process under control

Answer 9

- Rb hypophosphorylated - E2F transcription factors bind to RB - receives possitive growth signals - stimulated cyclin D and kinase → CDK4 + CDK6 which now phosphorylate rb - RB now hyperphosphorylated - Cells can progress and enter s phase - E2F released and can enter nucleus - finds target promoters that have a specific sequence in them and binds to them. Drives transcription

Answer 10

-E7 degrades RB by binding to a motif called LXCXE CR2 - Induces degredation once it has binded to it - When you have HPV E7 binds to RB, constantly degrading it, and prevents its binding to E2F - so E2F is free to bind in the abscence of possitive growth signals to its target promoters and drive transcription of genes that are important for progression into S phase - allows cells to keep on dividing even wehn not stimulated to do so - Leads to dna damage and mistakes, this activated P53

Answer 11

- If the cell is stressed or experiencing negative growth signals, p16 or p21 are activated wich inhibit Cyclin D/Cdk4,6 to prevent Rb phosphorylation and arrest the cell at the G1 restriction point - P53 is a good sensor of stress. - It can sense damage and then induce cell cycle arrest or senesce or apoptosis or repair DNA damage. - But E6 degrades P53 by binding to host cell factor called E6AP. - This is a ubiquitin ligase and it ubiquitinates P53 resulting in its degradation. So cells no longer die when they are stressed.

Answer 12

- HBV is endemic in China, Indonesia, Nigeria, Taiwan and also high in rest of Asia and Africa – similar to distribution of Hepatocellular carcinoma – see graph. - When this was discovered the HPV vaccine was developed to prevent HBV associated cancer development. - HBV vaccine constitutes purified Hepatitis B virus surface antigen (HBsAg), licensed in US in 1979 - First cancer vaccine! - In US, successful at reducing HBV infection once at-risk population targeted - Introduced into Taiwan in 1984, all new-born babies vaccinated against hep b virus to prevent mother-to-child transmission,

Answer 13

Incidence of Liver Cancer in Taiwan Pre- and Post- Vaccine (2009) - Introduced into Taiwan in 1984, all new-born babies vaccinated against hep b virus to prevent mother-to-child transmission, - Data from this study: - Incidence of HCC shown in orange in people born before 1984 and so were not vaccinated vs incidence of same cancer in those born after 1984 and so were vaccinated. - HBV vaccine is cheap, stable, easy to administer, immunostimulatory, works very well.

Answer 14

- Many people are vaccinated against HPV. - Cervical cancer incidence has dropped in develop countries because We have a good cervical screening programme: - HPV infects the SCJ cells of the cervix. - So when a cervical pap smear is taken the brush that is used targets these cells. - Prior to a change these cells were taken and sent off for histological analysis and pathologist would look at them to determine if they looked abnormal or normal. - The presence of virus is the cause of abnormal histology. - This has been successful for reducing burden of cervical cancer for women in UK - I.e. Cytological abnormalities in the cervix monitored by the “cervical smear” or “Pap” test

Answer 15

- Cervical cytology initiated in 1940s but was very sporadic and not well coordinated - 1988 saw emergence of a “true” programme. - Commences at 25 years – then called back every 3 years until 50 – then every 5 years, until 64 - Registration in central computer database known as the ‘Exeter’ system. - Interlinked “failsafe” processes - now, research has shown that HPV is an important driver of cervical cancer so now instead of doing cytology which can be subjective, the samples are sent for presence of virus instead via DNA testing. - Then only if sample is +ve is the cell cytology is looked at

Answer 16

Established properly in late 1980s - incidence of invasive cervical cancer has correspondingly dropped due to screening programme.

Answer 17

- If women are sent for HPV testing then you catch every single case of HPV drive disease at an early stage - so the incidence of invasive carcinoma (CIN3) is very low if women are tested for just HPV or combined HPV and cytology. - But if they do not do either then the incidence of cancer is much higher overtime.

Answer 18

- Developed from proteins that are expressed on capsid of HPV virus particle

Answer 19

- It is difficult to know that the vaccine is working as the target vaccination age is teenagers - we want to vaccine people before they become sexually active as it is a prophylaxes vaccine - need to have it before you become infected - once you are infected virus lays dormant - actual incidence of cervical cancer peaks much later in life. - People before infected early in sexual onset but only develop cancer in 50-60s. - So working out whether vaccine is having any effect is difficult as 40yr latency period. So yes it is working but expensive and not routinely used in developing countries where the need is greatest.

Viruses and Cancer Flashcards

(43 cards)