Lecture 9 - Viruses and Cancer

What is a viral permissive state?

All viral genes are expressed

What is a viral non-permissive state?

Viral genome is usually integrated into the host genome

• Some genes may be expressed but not structural genes 

What are the three main mechanisms of cellular transformation by viruses?

• Acutely transforming 

• Insertional mutagenesis 

• Transactivating transformation 

What is acutely transforming cellular transformation?

• Transfer deregulated oncogenes into host genome 

• No examples in humans 

What is insertional mutagenesis cellular transformation?

• Insertional mutagenesis into or close to a proto-oncogene/tumour suppressor gene 

• Rare in humans 

What is transactivating transformation cellular transformation?

• Viral gene expression affects host cell function  

  • Loss of host cell function 

What are endogenous retroviruses?

Retroviral elements which are found in the human genome.

• ~8% of the genome

• Their role in cancer is unclear 

What is the basic life cycle of an RNA virus?

• Virus binds its target receptor 

• Virus plasma membrane fuses with host cell membrane 

• Capsid is released into the host cell 

• Capsid uncoats and genome is released 

• Genome is reverse transcribed and integrated into the host genome 

• This can then disrupt proto-oncogene/tumour suppressor gene expression 

What are the three basic genes found in retroviral genomes?

GAG gene

• Capsid

POL gene

• Polymerase/Reverse transcriptase 

ENV gene

• Envelope gene

How do acutely transforming retroviruses form?

• Genome of infectious virus that’s not transforming integrates into host genome and captures a proto-oncogene 

• Causes formation of viral genome which now contains a proto-oncogene 

• If a mutation occurs in the proto-oncogene it can become an oncogene 

• This allows transformation of subsequently infected cells 

X-SCID is caused by mutations of what gene?

IL2RG mutations.

Retroviruses were used to insert functional IL2RG genes into patients with X-SCID.

What issue did this cause?

Insertion of the gene was random.

• In some patients the gene disrupted proto-oncogenes/tumour suppressor genes

• Resulted in leukaemia development 

How does Human T-cell Leukaemia Virus type-1 (HTLV-1) result in transformation of cells?

Expression of viral oncoproteins, REX and TAX

• These disrupt IL-2, IL-2R and GM-CSF signalling 

HIV is directly oncogenic once it infects individuals.

True or False?

False.

Very little evidence that HIV infection is directly oncogenic 

• Malignancy can develop because of AIDS resulting from HIV 

What type of cancer is strongly associated with AIDS development?

Kaposi’s sarcoma

How does hepatitis C infection increase the risk of cancer development?

Associated with hepatic cirrhosis and hepatocellular carcinoma

• Indirect mechanism of transformation due to liver cirrhosis and inflammation.

What can greatly increase the transformative capabilities of Hepatitis B?

Synergy with aflatoxins from aspergillus infected nuts.

How do HBV and Aflatoxins synergise to cause cancer?

• Toxin binds DNA which allows point mutations to develop when cells replicate at a high rate (HBV infected cells) 

• This causes mutations to occur allowing mutagenesis to occur 

What two types of HPV are oncogenic?

HPV-16 and HPV-18

What are the two oncoproteins expressed by HPV-16/18 which cause transformation? 

E6 and E7

What is the function of E6?

Binds p53 and inhibits it by targeting it for degradation 

• Allows cell cycle arrest to be stopped

What is the function of E7?

Binds to Rb and inhibits it

• Allows cell cycle to progress constantly 

How are HeLa cells an example of HPV’s insertional mutagenic potential?

Cells contain integration of HPV-18 sequence close to the c-MYC gene on 8q24 

What is Epidermodysplasia verruciformis?

Autosomal recessive disorder which causes uncontrolled tissue growth in response to HPV infection.

• Often caused by HPV-5 and -8

Lifetime increased risk of developing skin cancer (50%)

Epstein-Barr virus is associated with what type of cancer?

Burkitt’s Lymphoma

What synergises with Epstein-Barr virus?

Malaria.

Cause development of Burkitt’s lymphoma  

• Via B-cell proliferation and c-MYC translocation 

What viral oncoproteins does HPV-8 express which influence cell function?

LANA

• Inpairs host p53 and Rb function

V-Cyclin (homologue of cyclin D1)

• Binds cyclin dependant kinases and causes cell cycle progression

V-Flip

What are co-factors of Merkel cell polyomavirus (MCV) cancer development?

Exposure to UV light and immunosuppression. 

What percent of Merkel Cell Carcinoma contain the viral genome of Merkel cell polyomavirus?

80%

• However, viral infection is common and most people do not develop cancer