Viruses & neoplasia Flashcards
What are examples of retroviruses (RNA viruses) that cause cancer?
Avian leukosis virus – lymphoid, myeloid tumors, sarcomas
Feline retroviruses – lymphoid tumors
Jaagsiekte sheep retrovirus (JSRV) – lung adenocarcinoma
Bovine leukosis virus (BLV) – lymphoma
What are examples of DNA viruses that cause tumours?
Marek’s disease virus (herpesvirus) – lymphoid tumours
Papillomaviruses – cause skin & mucosal warts & papillomas in cattle, horses & dogs
What is a proto-oncogene?
Normal gene that can become oncogene due to mutation or increased (uncontrolled) expression
What are examples of proto-oncogene functions?
Receptor kinases
Adaptor proteins
Small binding proteins
Kinases
Transcription factors
How do proto-oncogenes become oncogenes?
Most cellular proto-oncogenes are normal components of growth factor signalling pathways
But…increased activity leads to increased cell growth:
- Mutation of proto-oncogene (cellular oncogene or c-onc)
- Viral transduction of an oncogene (v-onc)
- Viral insertion affecting production of cellular oncogene
What are the main mechanisms by which retroviruses cause cancer?
Transduction of an oncogene
Insertional activation of a cellular oncogene
Other mechanisms via specific viral proteins
How does retroviral transduction lead to cancer?
Retrovirus carries cellular oncogene & inserts it into host genome
This oncogene is overexpressed, leading to uncontrolled cell growth
How does a retrovirus integrate into the host genome?
- Virus enters host cell via receptor
- RNA genome is reverse transcribed into cDNA
- cDNA enters nucleus & is integrated into host genome using viral enzyme integrase
- Once integrated, viral genome remains in host for life, unless cell dies
What happens when a retrovirus acquires a cellular oncogene, and why are most defective oncogenic retroviruses not transmitted?
They often lose essential genes, making them “defective” & unable to replicate independently. As a result, they arise de novo in each infection & are not passed to new hosts
How is Rous Sarcoma Virus (RSV) different from other oncogenic retroviruses?
RSV can still replicate & transmit despite carrying oncogene, unlike most defective oncogenic retroviruses
What oncogene does RSV contain, and how does it cause cancer?
RSV carries v-src (viral homolog of c-src with C-terminal deletion) making it constitutively active & leading to uncontrolled cell growth
How does Rous Sarcoma Virus (RSV) cause rapid oncogenic transformation?
RSV carries v-src oncogene, which promotes uncontrolled cell division, leading to rapid transformation of normal cells into cancerous ones
What are key cellular changes after RSV infection?
Loss of contact inhibition (cells no longer stop growing when they touch each other)
Increased cell density (cells pile up abnormally)
Increased growth rate
Anchorage-independent growth (cells grow without needing a solid surface)
Tumorigenicity (cells can form tumours in appropriate hosts)
What type of retrovirus is RSV classified as?
Acute transforming retrovirus, meaning it induces cancer quickly due to direct oncogene activation
What is insertional activation in retroviral oncogenesis?
Retrovirus integrates near proto-oncogene (c-onc), leading to its abnormal activation & potential cancer formation
Process of oncogenesis is slower compared to acute transforming retroviruses
How do retroviruses cause cancer through insertional activation?
Unlike transducing retroviruses, these retroviruses don’t carry oncogene
Instead, their Long Terminal Repeat (LTR) regions act as promoters & enhancers, increasing transcription of nearby proto-oncogenes
What are the two main ways retroviral insertion can activate a proto-oncogene?
Promoter activation – viral LTR promoter enhances transcription of proto-oncogene
Enhancer activation – viral LTR enhancer elements increase expression even if insertion is some distance away
What is an example of an insertional activation retrovirus?
Feline leukemia virus (FeLV) & Avian Leukosis virus
How is avian leukosis virus transmitted?
From the hen to the egg
Chicks hatch with persistent infection & become immunotolerant to viral antigens & develop tumours
Incubation period for tumour development is > 4 months
What type of tumors does Avian Leukosis Virus (ALV) cause?
ALV primarily causes B-cell tumours, including:
- Tumours in bursal follicles (due to viral integration activating proto-oncogenes)
- Diffuse liver tumors (resulting from viral recombination & gene capture)
How is ALV controlled?
Control by eradication in breeder flocks
- Select virus-free hens by screening eggs before hatching
- Check eggs over 14-day period for ALV antigen in albumen by ELISA
- Hatch chicks and rear in isolation
- Test for ALV antigen in blood
- Maintain virus-free breeders
Virus is susceptible to disinfectants but can be transmitted by mating
What is Bovine Leukemia Virus (BLV), and how does it cause disease?
BLV is delta retrovirus that infects B lymphocytes, leading to enzootic bovine leukosis
Virus becomes latent in host genome, meaning there is no free virus in blood, but infected cattle produce antiviral antibodies
What viral protein is responsible for BLV-induced oncogenesis, and how does it work?
Tax protein transactivates cellular genes, promoting uncontrolled cell growth
Products of these transactivated genes may be oncogenic, contributing to lymphoma formation
How does the Tax protein contribute to cancer development?
Activates cytokine genes (e.g. IL-2, GM-CSF), promoting immune cell proliferation
Upregulates IL-2 receptors, creating positive feedback loop for continuous growth signals
Disrupts cell cycle regulation & causes chromosomal instability, increasing risk of transformation
How is BLV transmitted?
Via infected cells (e.g. milk, blood)
Can spread vertically (mother to calf) or horizontally
What disease does Jaagsiekte Sheep Retrovirus (JSRV) cause?
Ovine Pulmonary Adenocarcinoma (OPA) (“panting sickness”)
How does Jaagsiekte Sheep Retrovirus (JSRV) cause cancer?
Viral Env protein activates cellular signaling pathways, leading to uncontrolled cell division in type II pneumocytes & Clara cells
What are key respiratory signs of Jaagsiekte Sheep Retrovirus (JSRV) in infected sheep?
Loss of condition
Dyspnea (panting, difficulty breathing)
Clear or frothy lung fluid discharge
Slow progression, sudden death possible
How is JSRV transmitted and controlled?
Spread through respiratory secretions & requires close contact
More common in housed sheep
Controlled through isolation and culling
Diagnosis via histopathology and RT-PCR
What is a common DNA virus causing tumours in cattle?
Bovine papillomatosis caused by bovine papillomavirus (BPV)
Virus is tropic for epithelial and mucous tissues
How does bovine papillomavirus (BPV) persist and contribute to cancer development?
BPV establishes persistent infection & remains latent in host cells
Over time, expression of early viral genes activates host signaling pathways, leading to abnormal cell growth
What factors increase the risk of BPV-associated cancer?
Bracken fern exposure induces immunosuppression & genetic changes, weakening immune response & promoting neoplastic transformation
Why is BPV-associated cancer relatively rare?
Neoplastic progression is slow, multistep process, requiring additional factors like immune suppression & long-term viral persistence for tumour formation
What viruses are associated with alimentary and bladder cancers in cattle?
BPV-2: Causes bladder carcinomas & enzootic haematuria
BPV-4: Leads to alimentary carcinomas in oesophagus, rumen & reticulum
What disease does Marek’s Disease Virus (MDV)/Gallid herpesvirus 2 cause?
T-cell lymphomas in poultry
How is Marek’s Disease Virus (MDV) transmitted?
MDV is shed from feather follicle cells & spreads through dander & dust, which is inhaled by other birds, infecting respiratory tract
After inhalation, where does MDV disseminate in the body?
Virus spreads via blood to immune organs:
- Bursa of Fabricius
- Thymus
- Spleen
What are the clinical signs of Marek’s disease?
Neurological signs (paralysis)
Tumors in muscles and organs
Ocular changes
Immunosuppression
Cutaneous nodules
What are the effects of MDV on different immune cells?
B cells & macrophages → Undergo cell death, leading to immunosuppression
T cells → Initially undergo activation & proliferation, then transform into tumour cells, causing lymphomas
What are the three types of virus interactions with host cells in Marek’s disease?
Differ depending on cell type
Cytopathic (lytic) & cell-associated – Virus kills B-cells & macrophages
Non-productive (latent) & cell-associated – Virus remains in tumour cells in T lymphocytes
Cell-free & productive – Virus spreads from feather follicle cells, key source of infection
What factors make Marek’s Disease epidemiology complex?
Carrier status (latency)
Environmental survival for months
Viral virulence (mild to highly virulent strains)
Host factors, including MHC-dependent immune response & stress levels
How is Marek’s Disease diagnosed?
Clinical signs & pathology
Virus isolation, PCR & antibody detection (supportive but not confirmatory in absence of characteristic clinical signs)
Differential diagnosis is avian leukosis (doesn’t cause neurological signs)
What are the main strategies for controlling Marek’s Disease?
Disinfection, biosecurity & all-in-all-out management
Vaccination using:
- Turkey herpesvirus (HVT)
- Gallid herpesvirus-3 (SB-1 strain)
- CVI988/Rispens (attenuated Gallid herpesvirus-2)
How is Marek’s Disease vaccination administered, and how long does immunity take to develop?
Given in-ovo (before hatching) or to day-old chicks
Immunity takes 7 days to develop
What is the function of the gag gene in a retrovirus?
Gag gene encodes structural proteins, including:
- Matrix protein
- Capsid protein
- Nucleoprotein
These proteins form virus structure & protect viral RNA
What is the function of the pol gene in a retrovirus?
Pol gene encodes key enzymes needed for viral replication, including:
- Reverse transcriptase (converts viral RNA into DNA)
- Integrase (helps insert viral DNA into the host genome)
- Protease (processes viral proteins for assembly)
What is the function of the env gene in a retrovirus?
Env gene encodes viral envelope proteins, which help virus attach to & enter host cells
What are Long Terminal Repeats (LTRs) and how do they contribute to viral oncogenesis?
LTRs are repeating sequences at both ends of viral genome that contain promoter & enhancer regions, which regulate gene expression
LTRs can:
- Increase viral gene expression.
- Disrupt normal cellular gene regulation when virus integrates into host genome
- Activate oncogenes if they insert near proto-oncogene, leading to uncontrolled cell growth
What are endogenous retroviruses?
Proviruses integrated into host genome. If they enter germ cells (sperm or eggs), they are inherited by next generation; if in somatic cells, they are lost when animal dies
