Download - 12. Tumor Viruses and Slow Viruses
-
7/27/2019 12. Tumor Viruses and Slow Viruses
1/27
1
Tumor viruses /Oncogenicviruses
-
7/27/2019 12. Tumor Viruses and Slow Viruses
2/27
2
Viruses implicated in human cancersVirus Tumor Possible cofactors
DNA viruses Human papilloma
viruses(HPV)
Epstein-Barr virus
(EBV)
Kaposis sarcoma
herpesvirus (HHV-8)
Hepatitis B virus
(HBV)
Carcinogenesis of skin,
genitalia, larynx
Burkitts lymphoma
Nasopharyngeal carcinoma
- B-cell lymphoma
- Kaposis sarcoma
Hepatocellular carcinoma
(HCC)
Sunlight, smoking
Malaria
Nitrosamines in diet, taking of
snuffs with phorbol esters,
genetic factors
Immunosuppression
HIV infection
Liver cirrhosis/alcoholism,
food with aflatoxin
RNA viruses
Human T-cell
lymphotropic virus
(HTLV-I)
Hepatitis C virus (HCV)
Adult T-cell leukaemia/
lymphoma
Hepatocellular carcinoma(HCC)
Liver cirrhosis
-
7/27/2019 12. Tumor Viruses and Slow Viruses
3/27
3
General features of viral oncogenesis
Normal growth must be regulated so that tissues, organshave organized shape, size and function
They do not hypertrophy uncontrollably when cellsdamaged by disease or other factors
In normal cells genes are responsible for suppressing aswell as stimulating the growth
Deletion or mutation of these genes may producemalignant changes
Carcinogens induce oncogenic mutation
Some viruses can also act as mutagenic agents
Carcinogens can also act as cofactors along with these
oncogenic viruses
-
7/27/2019 12. Tumor Viruses and Slow Viruses
4/27
4
General features of viral oncogenesis
During viral oncogenesis
Oncogene is inserted into host cell DNA
Insertion is irreversible
This may or may not result in tumor formation
Some cofactors induce the oncogene andactivate it resulting in malignant state
-
7/27/2019 12. Tumor Viruses and Slow Viruses
5/27
5
Viral Oncogenes
Some of retroviruses (HTLV-I) possess a
special gene called oncogene (v-onc)
This gene is capable of conferring
malignancy on host cell
-
7/27/2019 12. Tumor Viruses and Slow Viruses
6/27
6
Mode of action
Retrovirus attaches to specific receptors on the hostcell
Then virion uncoats in cytoplasm
Viral RNA is converted to DNA by reversetranscriptase
Viral DNA (provirus) is integrated into host cellgenome
Sometimes integrated viral DNA containingoncogene (v-onc)
May get activated due to several factors and results information of oncogenic product.
-
7/27/2019 12. Tumor Viruses and Slow Viruses
7/27
7
Mode of action
Example Phosphorylating enzyme (protein kinase), an
oncogenic product
May modify the activity of various cell proteins which areinvolved in stimulation and suppression of cell growth
Such modifications will lead to a transformed cell, byclonal expansion , forms malignant tumor
During this process transformed cell acquires new tumorantigens (T) in its cell membrane
There are differences in the time taken for transformingviruses to produce oncogenic effects
Some viruses are slow and some are fast.
-
7/27/2019 12. Tumor Viruses and Slow Viruses
8/27
8
Cellular oncogenes:
Normal cells also have genes similar to viral oncogenes (v-onc)
They are called proto-oncogenes (c-onc)
In the cell these genes perform normal function
But when viral oncogene is inserted adjacent to cellularoncogene (c-onc), may indirectly leading to malignantchange in host cells.
This is called insertional mutagenesis
Cellular oncogene (c-onc) may acquire oncogenecity by mutationdue to carcinogens
Due to mutation in growth suppressor gene, may lead touncontrolled cell proliferation resulting in tumor
-
7/27/2019 12. Tumor Viruses and Slow Viruses
9/27
9
Indirect mechanisms
Cell regeneration:
In hepatocellular carcinoma(HCC) caused byHBV, viral genome is integrated at variable sites inhepatocytes.
So insertional mutagenesis is difficult
In HCC, cirrhosis leads to abnormal cellular
proliferation resulting in tumor
In HSV infection, there is proliferation of mucosalcells, in combination with other factors give rise tocarcinoma of cervix.
-
7/27/2019 12. Tumor Viruses and Slow Viruses
10/27
10
Indirect mechanisms
Immunosuppression:
Immunodeficient patients have an increasedliability to cancer
Because the immune surveillance system loses itscapacity to recognize cells with new tumor antigens asforeign.
Other factors:
Genetic, dietary, hormonal factors are alsoimplicated in some malignancies
-
7/27/2019 12. Tumor Viruses and Slow Viruses
11/27
11
Slow virus infections & Priondiseases
-
7/27/2019 12. Tumor Viruses and Slow Viruses
12/27
12
Slow virus infections
Some chronic degenerative diseases of CNS in humansare caused by slow or chronic, persistent infections byviruses
Papovavirus,
Retrovirus
Some strains of measles virus
The diseases include Subacute sclerosing panencephalitis (SSPE)
Progressive multifocal leukoencephalopathy
-
7/27/2019 12. Tumor Viruses and Slow Viruses
13/27
13
Subacute sclerosing panencephalitis
(SSPE)
Rare disease of adults with slowly progressive
demyelination in CNS ending in death
Virus is persistently infected in neural cells
It is caused by a Measles virus variant.
-
7/27/2019 12. Tumor Viruses and Slow Viruses
14/27
14
Progressive multifocal Leukoencephalopathy
JC virus, member of Papovavirus is the etiologic
agent
It is a CNS complication that occurs inimmunosuppressed patients
It is also associated with CNS demyelination
It is associated with AIDS patients
-
7/27/2019 12. Tumor Viruses and Slow Viruses
15/27
15
Prions
Prions are unusual infectious agents associated with anumber of diseases
Degenerative changes in the brain leading to spongiformencephalopathies
Lacks a nucleic acid genome and is highly resistant to allconventional forms of disinfection processes
Small proteinaceous particles, thought to be modified
forms of a normal cellular protein
Cause disease by converting normal protein into furtherabnormal forms
-
7/27/2019 12. Tumor Viruses and Slow Viruses
16/27
16
Prions
Transmission to humans is by ingestion of contaminatedmaterial
But infection can also be acquired through medical procedures
The first human prion disease identified was kuru,transmitted by ritual practices in New Guinea tribes
Involving consumption of human tissue
More recently human disease (new variant Creutzfeldt-Jakobdisease)
Mad cow disease has been associated with eating beef from cattleinfected with prion that causes bovine spongiform encephalopathy.
-
7/27/2019 12. Tumor Viruses and Slow Viruses
17/27
17
Prions
Pathological changes include development of
large vacuoles in CNS
Size is
-
7/27/2019 12. Tumor Viruses and Slow Viruses
18/27
-
7/27/2019 12. Tumor Viruses and Slow Viruses
19/27
19
Relationship between prion (PrPCJD) and
normal cellular prion (PrPC)
PrP refers to prion protein
There are small glycoproteins called PrPC are present innormal nerve cell surfaces
They do not have any apparent function
Prion protein CJD (PrPCJD) and cellular prion protein(PrPC) are closely related.
PrPCJD are infectious agents
PrPCJD are globular and enzyme resistant
PrPC are linear and enzyme susceptible.
-
7/27/2019 12. Tumor Viruses and Slow Viruses
20/27
20
Relationship between prion (PrPCJD) and
normal cellular prion (PrPC)
The proteins have similar sequence
Normal cells expresses PrPC in cell surfaces. FreePrPCJD interacts with PrPC.
This results in the release of PrPC from cell membrane.Then PrPC is converted into PrPCJD.
The host cell produces more PrPC which in turn will beconverted into PrPCJD
Accumulated as plaques and they are internalized bythe cells.
This will lead to slow degeneration of nerve cells andformation of spongiform vacuolation in brain tissues
-
7/27/2019 12. Tumor Viruses and Slow Viruses
21/27
21
Human Infection
CJD Has incubation period of 20 to 30 years
It is characterized by dementia and recurrent seizures
Death usually occurs within few months of onset
The brain also shows pronounced astrocytosis andneuronal loss
In some cases amyloid plaques are also present
Inadequately sterilized neurological instruments have also
accounted for transmission CJD cases have been reported in corneal transplant from
patient with CJD
CJD can also be transmitted to primates and other
animals
-
7/27/2019 12. Tumor Viruses and Slow Viruses
22/27
22
Human Infection contd.
Inherited spongiform encephalopathies
It resembles CJD and they are familial
Gerstmann-Straussler-Scheinker disease (GSSD)resembles CJD, here ataxia is a prominent feature
Fatal familial insomnia (FFI) is marked by severe
disturbances of sleep and atrophy and gliosis of medial
thalamus
These are rare and inherited disorders.
-
7/27/2019 12. Tumor Viruses and Slow Viruses
23/27
23
Human Infection contd.
Kuru:
It is a progressive and fatal dementia with cerebellarinvolvement leading to difficulty in walking
This disease is limited in for tribe of Papua New Guineaand spread by cannibalism
During which brains of dead relatives were eaten by others
Now virtually eliminated
Kuru is transmitted to a number of species of primates.
-
7/27/2019 12. Tumor Viruses and Slow Viruses
24/27
24
Animals Infection
Scrapie:
It is a spongiform encephalopathy affecting sheepand goats
The infected animal shows characteristic intenseitching
It is transmitted directly or indirectly from animal toanimal and acquired at birth
Incubation period is 1-5 years.
-
7/27/2019 12. Tumor Viruses and Slow Viruses
25/27
25
Animals Infection contd.
Other prion diseases of captive domestic animals
Bovine spongiform encephalopathy is a mostserious transmissible spongiform encephalopathy(TSE)
Can be transmitted from cattle to humans
Consumption of BSE infected meat (beef) may lead tomad cow disease which is due to new variant CJD(nvCJD).
-
7/27/2019 12. Tumor Viruses and Slow Viruses
26/27
26
Pathogenesis:
Prions first appears in blood then the agent multiplies inspleen and reticuloendothelial system,
It spreads to CNS through peripheral nerves to spinal cord
and brain
Cerebellum is particularly affected
It produce spongiform lesions, astrocytosis and amyloid
plaques in neural tissues
Brain tissues also show clusters of prion rods (fibrilformation).
-
7/27/2019 12. Tumor Viruses and Slow Viruses
27/27
27
Laboratory diagnosis
Immunoassay of a protein called 14-3-3 (or
P130/131) in CSF
It is present in all cases of CJD
But it is not specific for CJD