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Tumor viruses /Oncogenicviruses

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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

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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

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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

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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

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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.

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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.

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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

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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.

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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

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Slow virus infections & Priondiseases

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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

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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.

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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

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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

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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.

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Prions

Pathological changes include development of

large vacuoles in CNS

Size is

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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.

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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

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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

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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.

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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.

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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.

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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).

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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).

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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