Viruses and Cancer Flashcards
What did Peyton Rous discover?
- Chicken Sarcoma Virus in 1909
- Tumours found in the muscles of chickens which are transmissible by viruses
How did he discover chicken sarcoma virus?
- Removed sarcoma from the breast of a chicken
- Broke it up into small chunks of tissue
- Ground it with sand
- Passed it through a fine pore filter to collect filtrate
- Injected filtrate into young chickens
- Observed sarcoma in injected chicken
What is rous sarcoma virus?
- a retrovirus which has an extra gene called SRC
- Causes sarcoma in chickens
What is the difference between a DNA virus and a retrovirus
A DNA virus injects its own DNA into a host cell straight into the genome, however a retrovirus is a type of RNA virus which has RNA that needs to be reverse transcribed into DNA before it can enter the genome
What is an acute/chronic virus?
- Acute = occur suddenly and either resolve quickly or result in death
- Chronic = persists over a long period of time (6+ months)
Give an example of an acute and a chronic virus
- Acute = SARS-CoV2 (Covid)
- Chronic = Human Immunodeficiency Virus (HIV)
What is a cytopathic/non-cytopathic viru
- Cytopathic = either completely eliminated by the immune system or they kill the infected organism
- Non-cytopathic = can establish long-lasting infections and successfully evade complete destruction by the immune system
Give an example of a cytopathic and a non-cytopathic virus?
- Cytopathic = influenza virus
- Non-cytopathic = Hepatitis C virus (HCV)
What are examples of chronic virus infections associated with human cancer?
- Hepatitis B virus (HBV)
- Hepatitis C virus (HCV) (RNA virus)
- Epstein Barr virus (EBV)
- Human herpes virus-8 (HHV-8)
- Human papilloma virus (HPV)
- Human T cell lymphotropic virus (HTLV-1)
- Polyoma virus
What are 2 ways in which chronic viral infections cause cancer?
- Immortalisation of cells followed by secondary mutation due to DNA damage
- Chronic inflammation leading to multiple cycles of tissue repair
What is immortalisation?
The ability of a cell line to reproduce indefinitely. The cells escape from the normal limitation of a finite number of division cycles which can lead to tumour formation
What percentage of human cancers are associated with viral infections?
- Approx 40%
- specifically liver and cervical cancers and Lymphomas
What did Hansen discover between HPV and cervical cancer?
- Cervical carcinoma lesions derived from benign lesions are histologically similar to warts and other papillomas
- Found that HPV DNA is found within cervical carcinomas
- Now it’s known that approx 80-90% of cervical cancers are associated with HPV16 and/or HPV18
What are some characteristics of HPV?
- Known to consist of 150+ genotypes
- Sexually transmitted
- Some of these genotypes (eg HPV16/HPV18) are associated with cervical cancer
- Some are associated with warts of specific tissues
What are some cancers that oncogenic HPV is associated with?
- Anogenital
- Oropharyngeal
- Oesophageal
How does HPV cause cancer?
- Causes cells to undergo change and if they’re not treated they can, over time, become cancer cells.
- Once oncogenic HPV infects cells, it interferes cell communication, causing infected cells to multiply in an uncontrolled manner leading to tumours
How does HPV infiltrate the body?
- Virus infects a basal keratinocyte in the epidermis with the use of early (E) genes
- The virus and cells replicate together
- Viral DNA is amplified in non dividing cells
- Using late (L) genes, the virus is made ready for infection of the individual
What vaccines are there to protect from HPV?
- Cervarix -> HPV16/18
- Gardasil -> HPV16/18/6/11
- Has lead to a large reduction in cervical cancer
Does SV40 polyoma virus cause cancer in humans?
- Simian virus 40 (SV40) is a type of Polyoma virus
- Infects monkeys and causes cancer in hamsters
- In US 1955-1963 90% children and 60% adults were inoculated with SV40-contaminated polio vaccines
- However there were no epidemiological links to cancer
- SV40 does infect human lung mesothelial cells, not sure if it causes mesotheliomas
Do JCV/BKV polyoma viruses cause cancer?
- Both cause brain tumours in hamsters
- Both infect nearly all humans by 11 years
- JCV can cause progressive multifocal leukoencephalopathy (PML) seen in AIDS
- JCV is associated with astrocytomas that arise in JCV-PML lesions
- Both cancers are very rare
Does MCV polyoma virus cause cancer?
- Merkel cell polyoma virus (MCV) causes brain tumours in hamsters
- Recently associated with Merkel cell carcinoma (aggressive skin cancer)
What are human herpes viruses (HHVs)
- 8 different viruses that all infect humans
- Lifelong infections which are controlled by immunity
- Are latent/reactivating = able to lie dormant in the cell for a period of time with no symptoms and then become reactivated and cause infections
What are the 8 HHVs?
- Herpes simplex virus type 1 (HHV-1)
- Herpes simplex virus type 2 (HHV-2)
- Varicella zoster virus (HHV-3)
- Epstein-Barr virus (HHV-4)
- Cytomegalovirus (HHV-5)
- Human herpesvirus 6 (HHV-6)
- Human herpesvirus 7 (HHV-7)
- Human herpesvirus 8 (HHV-8)
What is an example of symptoms caused by HHV-3?
Causes chicken pox in early life and then shingles in later life
What is the life cycle of a HHV?
- Virus enters and infects cell
- Virus replicates inside the cell
- Lytic infection causes the cell to die and the newly made viruses are released
- Process repeats
How does HHV become latent?
A HHV establishes latency inside a new cell by:
- It replicates closely to the host genome and only uses proteins it really needs
- This results in not many viral antigens being displayed on the cell surface
- The virus is then able to avoid immuno surveillance and replicate for years
- It can then reactivate and continue its usual life cycle
What are characteristics of EBV and HHV-8?
- Both gamma-herpes viruses
- Both linear dsDNA genomes
- long unique region of 140 kbp
- 85-100 ORFs
What are cancers associated with EBV?
- majority of people are infected but most don’t develop anything further
- there are rare cancers developed:
1. Lymphoma in immunosuppressed patients (HIV/transplant)
2. Burkitt’s lymphoma in Africa
3. Nasopharyngeal cancer is Asia
What are cancers associated with HHV-8?
- up to 40% of populations infected usually only causing a mild fever
- rare cancers include:
1. Kaposi’s sarcoma
2. Multi centric Castelman’s disease
3. Primary effusion lymphoma (PEL)
How do EBV and HHV-8 become latent?
- both can immortalise peripheral B cells
- they convert these cells into immortalised lymphoblastoid cells
- HHV-8 can also infect and immortalise keratinocytes, epithelial cells and vascular endothelial cells
- latent infection only requires a fraction of the viral genome to be expressed
How do EBV and HHV-8 cause Burkitt’s lymphoma?
- the immortalised lymphoblasts made by the virus continue to divide, making them prone to picking up secondary mutations
- this is a problem for these cells as B cells have a potent recombinase system which allows them to perform chromosomal rearrangements and translocations
- an overexpression of this causes translocations that result in the formation of oncogenes
- Burkitt’s lymphoma is an example of this as a common translocation is bringing c-myc (ch8) next to an IgG loci (ch14) leading to the dysregulation of c-myc and its transformation into an oncogene
How does HHV-8 cause skin cancer?
- vascular endothelial cells can be infected by HHV-8 which triggers their transformation into spindle cells
- HHV8 latently infect VE cells
- HHV8 uses ephrin receptor A2, which is expressed on VE cells, that result in ligation that triggers angiogenesis and transformation
- These lytically infected cells induce host production of paracrine factors which, with virus-encoded factors, promote proliferation of latently-infected cells, invasiveness and angiogenesis
What is viral hepatitis?
- An infection that causes liver inflammation
- associated with several pathogens (Hepatitis A/B/C/D)
- often acute infections, resolved by host immunity
- sometimes chronic infections, kept under control by host immunity
- chronic infections can lead to cirrhosis and eventually hepatic cancer
What is Hepatitis B virus (HBV)
- A DNA virus
- it is chronic hepatitis that leads to cirrhosis and can eventually progress to hepatocellular cancer (HCC)
- one of the most common malignancies in the world, especially Africa and Asia
How successful is the HBV vaccine?
- In Taiwan, carrier rate in children fell from 10% to 1.3% 10 years after mass vaccination
- HCC rate is falling and is expected to decrease by 85% within 3-4 decades of mass vaccination
What is Hepatitis C virus (HCV)?
- an RNA virus (ssRNA flavivirus)
- causes chronic hepatitis
- no vaccine at the moment
- good drugs to protect but are expensive
- non-Cytopathic
- associated with extensive liver infiltration of leukocytes
- associated with generation and infiltration of CD8+ cells which attack and destroy infected cells
- HCV persistence is due to variants which are not recognised by CD8+ cells
What is human T-cell lymphotropic virus (HTLV-1)
- an RNA virus (retrovirus)
- isolated from adult T—cell leukaemia (ATL)
- varies from smouldering leukaemia to aggressive lymphoma
- inserts randomly and is able to transactivate the hosts oncogenes to immortalise T cells and induce leukaemia/lymphoma
- less than 1 in 100 infected in a lifetime
