Viruses and cancer

Question 1

What are the two effects of viruses?

Answer 1

• can cause acute or chronic/persistant infections - SARS-CoV-2, EBV
• can cause cytopathic or non-cytopathic infections - influenza, HCV

Question 2

What chronic virus infections are associated with cancer?

Answer 2

• HBV
• HCV (RNA virus)
• EBV
• HPV
• HTLV-1

Question 3

What are the two ways in which chronic viral infections cause cancer?

Answer 3

• immortalisation followed by secondary mutation due to DNA damage
• chronic inflammation leading to multiple cycles of tissue repair
• 40% of cancers associated with viral infections

Question 4

Describe the Papilloma virus

Answer 4

• HPV known to consist of > 150 genotypes
• some of these are associated with cervical cancers - HPV16 and 18
• some are associated with warts of specific tissues
• the ‘oncogenic’ HPVs are also associated with anogenital, oropharyngeal and oesophageal cancers

Question 5

Explain the life cycle of papillomavirus

Answer 5

• virus infects basal cell layer (cells are actively dividing)
• establish themselves as replicating pools
• as cells progress, they become more differentiated

Question 6

How does cancer associate with integration of HPV into cellular chromatin?

Answer 6

• there are some hotspot of integration

- many integrations leads to up regulation of E6 and E7

Question 7

What vaccines are used against HPV?

Answer 7

• HPV 16, 18 = cervarix
• HPV 16, 18 + 6, 11 = gardasil
• dramatic reduction in cervical carcinoma

Question 8

Describe Polyoma virus : SV40

Answer 8

• infects monkeys , causes tumour in hamsters
• no epidemiological link to cancer
• SV40 infects human lung mesothelial cells; viral DNA found in mesotheliomas, unclear whether it is in any way causal

Question 9

Describe the polyoma virus - JCV, BKV

Answer 9

• JCV, BKV cause brain tumours in hamsters
• JCV and BKV infect nearly all humans by 11 years
• JCV cause progressive multifocal leukoencephalopathy (PML) seen in AIDS and other immune suppressed states
• JCV is associated with astrocytomas that arise in JCV-PML lesions

Question 10

What is Merkel cell polyoma virus?

Answer 10

• merkel cell polyoma virus causes brain tumours in hamsters

- merkel cell polyoma virus (MCV) recently associated with Merkel cell carcinoma (aggressive skin cancer)

Question 11

Describe the lifecycle of a herpervirus

Answer 11

• in primary infection, virus infects the cells, virus replicates, cells die = releases new virus
• new virus attempts to establish cell
• at some point immune system destroys virus and cells which express viral antigens
• viruses are able to establish latency
• one viral particle will establish itself in a cell and replicate in episome - low copy number
• avoiding immunosurveilance, not presenting many antigens
• can stay for years - immortalise cells its in
• continually regenerate = latency

Question 12

Describe EBV and KSHV/HHV-8

Answer 12

• rhadinoviruses
• other mammalian homologs (HVS, MRV)
• linear dsDNA genomes
• long unique region of 140kbp
• 85-100 ORFs

Question 13

Cancer associated with EBV

Answer 13

• majority of people infected, some develop infectious mononucleosis-glandular fever
• rarely get : lymphoma in immunosuppressed patients, burkitts lymphomas (africa), nasopharyngeal cancer (asia)

Question 14

Cancer associated with KSHV

Answer 14

• 1 in 40% of population infected causes a very mild fever

- rarely get : kaposi’s sarcoma, multi-centric castle-mans disease

Question 15

How do EBV and KSHV establish latent infections of B cell precursor populations?

Answer 15

• EBV and KSHV can both immortalise peripheral B cells
• converts peripheral B cells into immortalised lymphoblastoid cells
• KSHV can also infect and immortalise keratinocytes, epithelial cells and vascular endothelial cells
• latent infection requires only a fraction of the viral genome to be expressed

Question 16

Why do EBV and KSHV cause cancer?

Answer 16

• the continued division of virally immortalised lymphoblasts = prone to pick up secondary mutations. Especially a problem in B cells since these express a potent recombinase system and chromosomal rearrangements and translocations
• common translocation in Burkitts lymphoma is bringing c-myc next to an IgG loci on ch14 leading to dysregulation of c-myc = oncogene

Question 17

Why does KSHV cause skin cancer?

Answer 17

• vascular endothelial cells can be infected by HHV8 trigger transformation to spindle cells
• HHV-8 will latently infect VE cells
• HHV-8 uses the ephrin receptor A2, expressed on VE cells
• minority of HHV08 infected cells support lytic infection, albeit often abortive
• lytically infected cells induce host production of paracrine factors (VEGF) which together with virus-encoded factors promote proliferation of latently infected cells, invasiveness and angiogenesis

Question 18

Describe viral hepatitis

Answer 18

• associated with several pathogens called hepatitis virus A, B , C and D
• often acute infections, resolved by host immunity
• sometimes chronic infections, kept under control by host immunity
• chronic infections can leads to cirrhosis and eventually hepatic cancer

Question 19

Hepatitis B virus and liver cancer

Answer 19

• HBV is a DNA virus
• chronic hepatitis followed by cirrhosis can progress to hepatocellular carcinoma
• liver cancer - hepatocellular cancer
• once of the most common malignancies in the world mainly in asia and africa

Question 20

Describe the hep b vaccine

Answer 20

• in taiwan carrier rate in children fell from 10% to 1.3% 10 years after mass vaccination
• already rate of HCC is falling and is expected to decrease by 85% within 3-4 decades of vaccination

Question 21

Hepatitis C virus and liver cancer

Answer 21

• causes chronic hepatits/hepatoma
• no vaccine at present
• good drugs against HCV, but expensive

Question 22

Describe the immunopathology of hepatitis c

Answer 22

• chronic hepatitis is a disease of severe liver damage and loss of hepatocytes
• HCV is non-cytopathic
• hepatitis associated with extensive liver infiltration of leukocytes
• viral clearance and disease is associated with generation and infiltration of CD8+ cells which attack infected cells and destroy them
• HCV persistence is associated with the generation of HCV variants that are not recognised by CD8+ cells

Question 23

Human T-cell lymphotropic virus

Answer 23

• HTLV-1 isolated from adult T-cell leukaemia (ATL) a recent condition diagnosed in Japan in 1973
• ATL varies from smouldering leukaemia to aggressive lymphoma involving visceral and skin lesions

Question 24

Describe the pathogenesis of HTLV-1

Answer 24

• inserts randomly and is able to transactivate the hosts oncogenes and hence immortalise T cells to induce leukaemia and lymphoma