Lecture 6 - Viruses and Cancer

Question 1

Briefly describe the characteristics of viruses?

Answer 1

• enormous variety of structure and complexity
• comprise: genetic material, protein capsid, membrane envelope
• cannot reproduce independently of host cell
  Host cell functions required for:
• translation of viral mRNA
• genome transcription
• genome replication
  Virus replication normally results in cell death

Question 2

Give examples of some viruses, bacteria and liver flukes that are classified as carcinogenic to humans

Answer 2

Viruses
- Epstein Barr virus
- Kaposi sarcoma herpes virus
- hep C/hep B
- Human T cell lymphotrophic virus type 1
- human immunodeficiency virus type 1
- high risk human papulloona virus 
Bacteria
- helicobacter pylori
Liver flukes
- schistosomes haematobium
- opsithorchis veverini
- clonorchis sinensis

Question 3

What is the relationship between HIV1 and cancer?

Answer 3

• In HIV-1 infected individuals there is increased incidence of cancers caused by other infectious agents including viruses
• Immune system is compromised in HIV-1 infected patients enabling persistence of other infectious agents including the cancer causing viruses
• HIV-1 is an indirect carcinogen
• Immunosurveillance is important in controlling these infections - organ transplant recipients have increased incidence of cancers caused by infectious agents

Question 4

Causality is had to establish because virus-associated human cancers:
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Answer 4

• long latency period between primary infection and tumour development
• only small % of virus-infected individuals develop the tumour
• complex multistep pathogenesis
• virus infection is one link in a chain
• no experimental animal models for the human cancers

Question 5

What is the link between AIDS and Kaposi sarcoma virus?

Answer 5

A link was established

Took normal and tumour DNA and looked at differences –> identified an undiscovered virus

Question 6

What is merkel cell carcinoma?

Answer 6

neuroectodermal tumour arising from mechanoreceptor Merkel cells in skin

• very agressive
• evident in immunosuppressed people

Question 7

What is the link between viruses and merkel cell carcinoma?

Answer 7

Tumours found to contain a new virus - Merkel Cell Polyomavirus (MCPV0

• very common skin infection
• but only a small proportion of infected indiviudals will develop cancer
• structure of MCPV genome is often altered in cancer cells - clonal integration of viral genome (normally not integrated)

Question 8

What is the molecular mechanism between HPV and cancer?

Answer 8

HPV is a direct carcinogen

• encodes proteins which have a direct role in proliferation
• E6 and E7

Question 9

HPV life cycle is tightly linked to epithelial differentiation .
Explain

Answer 9

• HPV infects mitotically activate cells in basal layer, but undergoes vegetative replication in mitotically inactive suprabasal cells
• As cells move up the layers they enter G0 and begin to differentiate

Question 10

What is the role of E6 and E7 in cancer development

Answer 10

E6 and E7 work co-operatively to promote proliferation and cell survival of the infected cells –> viral genome replication –> progeny formation
E6 = downregulates p53
E7 = down regulates pRB
- Deregulation of these pathways promotes host genome instability –> increased risk of acquiring an oncogenic mutation
- leads to cancer development - persistent HPV infections

Question 11

Give an example of a viral vaccine that reduced incidence of cancer

Answer 11

Hepatitis B Vaccine

Reduced incidence of liver cancer dramatically

Question 12

What is the cervical screening programme?

Answer 12

Cytological abnormalities in the cervix monitored by the ‘cervical smear’ or ‘pap’ test
- registration in the central computer database known as the Exeter system - failsafe

Question 13

How was the HPV vaccine developed?

Answer 13

HPV16 L1 proteins expressed in insect cells

• assembled into empty particles
• this used as vaccine as contains not viral genome

Question 14

How many HPV vaccines are there?

How do they differ?

Answer 14

Cervarix and Gardasil

Protect against different strains

Question 15

What were the populations of interest in the HPV vaccine trial?
What is the population vaccinated now?

Answer 15

Naive population
- negative for HPV16/18 DNA and specific antibodies to the virus at enrolment
All comers
- unknown viral DNA and antibody status
NOW
- only naive pop, need to vaccinate prompt to infection with the vaccine target HPV types

Question 16

What are the 4 common characteristics of viral infection leading the cancer?

Answer 16

1. Common persistence infection in the general population - long latency period between primary infection and tumour development, only small % of infected develop the tumour
2. Incidence of virus-associated cancers increases in immunocompromised individuals
3. Complex multi-step pathogenesis - requirement of cofactors in development of virus-associated cancers
4. Virus infection is one link in the chain
   - viral genes that control cell proliferation, cell survival, immune regulation important in tumour development, break the link with prophylactic vaccines