Tumour Viruses

Question 1

Rous Sarcoma Virus

Answer 1

• Had 4 genes: 3 for replication and fourth for transforming cells
• Discovered by Peyton Rous: 1879-1970. Isolated the first tumour causing animal virus (in chickens)
• Awarded Nobel prize 55 years later in 1966,
• 20% of human cancers associated with viruses

Question 2

Oncogenes

Answer 2

An oncogene is a gene coding for proteins that can cause cell transformation:

• Some viruses carry their own oncogenes (e.g. RSV)
• Some viruses disrupt the host’s regulation of normal cellular genes involved in control of cell growth which can then act as oncogenes (proto-oncogenes) –> uncontrolled proliferation
• We can use experimental infections with these DNA and RNA viruses to identify genes involved in cancer development

Question 3

Normal Cell Cycle

Answer 3

1. The cell cycle is normally tightly regulated.
2. Specific checkpoints control progression through the cell cycle.
3. If certain criteria are not met, then checkpoints block progression through phases and apoptosis occurs (programmed cell death).

• Cells of skin & intestinal lining are almost always in growth phase
• Liver/ lung cells are mainly in the G0 phase but can enter growth phase when required
• Cells of heart muscle & CNS, don’t have resident tissue stem cells- heal by fibrosis/ scarring rather than tissue regeneration

Question 4

Cell Transformation

Answer 4

Characterized by: Uregulated Cell growth, Loss of Contact Inhibition, Altered Cell morphology

• Tumours are the result of unregulated cell proliferation,
• Caused by altered expression of genes that are involved in growth control:

1. Genes that are stimulatory for growth and which cause cancer when hyperactive (oncogene)
2. Tumour suppressor genes which are responsible for controlling the checkpoints (inhibit cell growth) are switched off –> dysregulation of cell checkpoints

Question 5

Papilloma Viruses

Answer 5

• Papillomaviridae
• Non-enveloped, dsDNA virus
• Species Specific
• Resisitant to diverse environmental insults
• Over 118 types

Question 6

Retroviruses

Answer 6

• Retroviridae
• Enveloped, RNA virus
• Possess unique enzyme reverse transcriptase- converts RNA–> DNA

Question 7

Papillomaviruses

(Pathogenesis)

Answer 7

• Entry via lesion in epithelium (skin or mucosa) & infect dividing basal cells below
• First theres expression of early proteins (oncogenes) in basal epithelial cells uncontrolled proliferation
• Differentiate & are sloughed off towards the surface epithelium, late structural proteins are expressed
• Virus transmission via exfoliated cells

Question 8

BPV Genome

(papillomaviruses)

Answer 8

divided into:

1. Early genes: non-structural proteins (in basal epithelium and transformed cells)

2. Late genes: structural proteins (differentiated cells)

Question 9

Diseases caused by Papilloma viruses

Answer 9

• Low Risk –> warts/verruca (HPV-1)
• High Risk –> cell transformation & malignant tumour growth e.g. Cervical Cancer (HPV-16/ HPV-18)

Question 10

Bovine Papilloma Virus

Answer 10

• In cattle 10 BPV recognised to date
• Usually benign skin tumours (papillomas) particularly on head, neck, shoulder and udder
• Most frequently in calves and yearlings
• BPV-1/5/ 6 –> fibropapillomas on teats, BPV-1 benign penis tumors, BPV-1/2 benign facial tumors
• In most cases tumours regress spontaneously after ~ 6 months, may persist if immunocompromised

Question 11

How early gene e5 contributes to transformation

(papilloma virus)

Answer 11

• Virus protein E5 binds to receptor for platelet-derived growth factor (PDGF)–> cell proliferation
• E5 inhibits the formation of gap junctions between cells –> ↓ communication of the infected cell with neighbouring cells and lack of growth inhibitory signals from those cells
• E5 downregulates MHC1 expression- helps virus evade host immunosurveillance

Question 12

Malignant Tumors

(papilloma)

Answer 12

• BPV-4 infection usually–> benign papillomas in GIT, but can –>malignant tumours in upper GIT & bladder in cattle grazing on bracken fern (contains mutagens & immunosuppressants)

Question 13

BPV in Horses–> SARCOIDS

(papilloma)

Answer 13

• BPV-1/2 E5 expression is associated with–> equine sarcoids
• locally invasive skin tumours
• Frequently recur after surgical removal & in some cases more severely
• Vary in gross appearance: verrucous, fibroblastic, occult, mixed
• Can mistake for ringworm/ granulation tissue
• Transmission from horse to horse has been shown experimentally
• Biting flies now thought to be involved in viral transmission
• The infection transformation of fibroblast (mesenchymal) cells in the dermis (not epithelial cells)

Question 14

Canine Oral Papillomavirus

Answer 14

• Benign tumours on lips, tongue, palate- Usually spontaneously regress

Question 15

Equine Papillomavirus

Answer 15

Causes benign skin tumours- Usually self-limiting

Question 16

Jaagsiekte Sheep Retrovirus

Answer 16

• Causes: Ovine pulmonary adenocarcinoma (tumour in lung epithelial cells)
• Similar arrangement of genome to FeLV but env (a structural protein) is the oncogene
• Pneumocytes line the alveoli:

Type 1 pneumocytes- where gaseous exchange occurs

Type 2 pneumocytes –>surfactants (progenitor cells of the lung)

• When sheep inhale JSRV infects type 2 pneumocytes –> env protein is expressed–> cell transformation
• Symptoms: ‘driving sickness’- respiratory distress, some weight loss, exercise intolerance
• Diagnosis: Wheelbarrow Test- lift hind legs higher than head & fluid produced by virus will leak out of nose
• Transmission: Virus–> fluid of lungs and is coughed up & spread on

Question 17

Retroviruses

Answer 17

Retroviruses commonly cause immunological disease, neurological disease, cancer

• Alpha Retroviruses –> RSV
• Beta Retroviruses–> JSRV (causes lung cancer in sheep), ENTV-1/2 (enzootic nasal tumour virus- sheep)
• Gamma Retroviruses–> FeLV
• Lentiviruses–> FIV & EIAV

Question 18

Retroviral Replication

Answer 18

• Bind to specific receptor–> cytoplasm
• Reverse transcription occurs: RNA–> ds DNA (DNA-RNA hybrid forms in between)
• (In some cases, cell must replicate for virus to gain entry through nuclear membrane- Can be an important limiting factor)
• Viral DNA integrates with host genome at random–> provirus
• Viral mRNA produced using host cell’s RNA polymerase

Question 19

Organization of Retroviral Genome

Answer 19

• LTR - (Long Terminal Repeats) at either end- regulate gene expression, can ↑ expression of host genes
• GAG - (Group specific antigen)- Codes for capsid
• POL- Codes for polymerase (reverse transcriptase)
• ENV- Codes for envelope proteins

Question 20

Cell Transformation

(retroviruses)

Answer 20

1. Some retroviruses carry oncogenes (v-onc) in the viral genome (e.g. JRSV)
2. Some retroviruses don’t carry oncogenes, instead activate a cellular proto-oncogene: i.e. viral DNA is inserted next to a cellular oncogene & LTRs cause upregulation insertional mutagenesis (FeLV)
3. May inactivate a tumour suppressor gene

Question 21

Feline Leukamaemia Virus (FeLV)

Answer 21

• FeLV –> tumours of lymphocytes (lymphoma)
• Transmitted oronasally in saliva (mutual grooming, sharing of bowls)
• 1% prevalence in individually kept cats, Up to 20% prevalence in multi-cat houses

Question 22

FeLV Pathogenesis

Answer 22

• Initial viral replication in the lymphocytes/ macrophages of hosts tonsils –> Primary viraemia
• Cat may show pyrexia/ generalised lymphadenopathy or maybe clinically normal
• Outcome of infection depends on: Age of animal & host immune response

Possible Outcomes:

• 20-30 % will seroconvert without becoming detectably viraemic.
• 30-40 % show transient viraemia & remain latently infected with provirus in the bone marrow cells. May reactivate if animal immunosuppressed but rare.
• 30% will become persistently viraemic: Virus infects dividing cells in the BM & integrates –> stem cells, large quantities released from bone marrow, infects epithelial cells in salivary glands & intestine & released. Clinical signs of immunosuppression, anaemia & lymphoma
• FeLV often integrates near c-myc gene –> uncontrolled expression of myc (protein regulates transcription) cell proliferation
• Tumours can originate in any organ: May be multicentric (involving lymphoid tissues at various sites) or may involve predominantly one site such as the thymus, alimentary tract or in rare cases: skin/ kidney
• Immunosuppression due to malfunction of lymphocytes –> secondary infections (which are most common cause of death in cats with FeLV)

Question 23

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