Slow Viruses, Prions; Oncogenic Viruses; Vaccines

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rare complication of measles virus infection and develops ~1-10 years after the initial infection. It is progressive and fatal and is characterized by mental and motor deterioration. Risk factors include acquiring primary measles at early age.

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SUBACUTE SCLEROSING PANENCEPHALITIS

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rare, progressive, fatal, demyelinating disease of the CNS which kills oligodendrocytes.


Results in memory loss, loss of co-ordination, entasia problems (spams), vision problems, etc.

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Progressive Multifocal Leukoencephalopathy

Front 3

Which virus associated with Progressive Multifocal Leukoencephalopathy
?

Back 3

JC Virus (Papova family)

Front 4

T/F Patients who develop PML frequently have some abnormality of the immune system.

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T. ~5% of AIDS patients get it

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very rare consequence of rubella virus infection and also results in mental and motor deterioration.

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Progressive Rubella Panencephalitis (PRP):

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What is the course of Progressive Rubella Panencephalitis (PRP)?

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The initial infection was usually congenital or soon after birth and the onset of PRP occurs at 8-19 years of age.

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Where does rabies virus replicate once it gets in via animal bite? Where does it then travel?

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First replicates in muscle at site of bite. Then travels via retrograde transport to PNS. Then gets in Dorsal root ganglion. Travels up spinal cord to brain.

Front 8

During the incubation/prodromal period, symptoms of rabies include:

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pain or itching at the site of the wound, fever, headache and gastrointestinal problems. After this period (usually of up to two weeks), CNS infection is apparent.

Front 9

What is seen after CNS infection of rabies starts?

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Hydrophobia (due to pain associated with drinking). There are also seizures and hallucinations. In some patients paralysis is the only symptom and this may lead to respiratory failure. Following the neurological phase, the patient becomes comatose. Because of the neurological problems including respiratory paralysis, death ensues.

Front 10

T/F Vaccination for rabies is extremely effective, but only before exposure.

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F. Effective even after exposure.

Front 11

What are the inclusion bodies associated with rabies?

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Negri bodies

Front 12

Prion diseases are also called ___________. Why?

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Transmissible Spongiform Encephalopathies or TSEs. Prions destroy brain tissue giving it a spongy appearance.

Front 13

What is the protein that gets rearranaged in scrapie? What is its normal function?

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The normal protein is called PrPC ( C- for cellular)
* It is a transmembrane glycoprotein normally found at the surface of certain cells (e.g., neural and hematopoietic stem cells)
* its secondary structure is dominated by alpha helices (probably 3 of them)
* is easily soluble
* is easily digested by proteases

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How are prions similar to viruses?

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Small, filterable, need host cells, no machinery for energy generation or protein synthesis.

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How are prions different from viruses?

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No detectable virions in target tissues, No detectable virions in purified material; if nucleic acid is present, very small. Very resistant.

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T/F There is no antigenicity to prions and therefore no immune response.

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T. There is no inflammation

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T/F Prions can be destroyed only by UV radiation

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F

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mutated PRNP gene may be responsible for development of what diseases?

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Creutzfeld Jacob Disease (CJD ), Fatal Familial Insomnia (FFI), Gerstmann-Sträussler-Scheinker disease (GSS)


They're all from different mutations.

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What is inheritance pattern of Creutzfeld Jacob Disease (CJD )

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autosomal dominant

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Gerstmann-Sträussler-Scheinker disease (GSS): what is it?

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very rare, usually familial, fatal neurodegenerative disease that affects patients from 20 to 60 years in age. This extremely rare disease is classified as a transmissible spongiform encephalopathy (TSE).

Due a mutation in PRNP

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Fatal Familial Insomnia (FFI): what is it?

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very rare autosomal dominant inherited prion disease of the brain. It is almost always caused by a mutation to the protein PrPC

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Scrapie is called ___________ in cows and __________ in humans

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Bovine spongiform encephalopathy/ mad cow disease; Creuzfeld Jacob

Front 23

Chronic wasting disease (CWD), a cousin of mad cow disease,
affects what species?

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Deer

Front 24

How do ingested prions reach the brain?

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Ingested prions may be absorbed across the gut wall at Peyers patches which include the Mucosal Associated Lymphoid Tissue (MALT).
Prions could be taken up in the MALT.
Lymphoid cells then phagocytose the PRIONS particle and migrate to other lymphoid sites such as nodes, the spleen and tonsils. The prion can replicate at these sites. Many of these sites are innervated and eventually the prion gains access to a nerve and then propagates back up the axon to the spinal cord and eventually the brain.

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Why don't the proteasomes destroy the misfolded proteins caused by prions like they destroy other misfolded proteins?

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It's thought that the sheer amount of misfolding overwhelms the proteasome.

Also thought to happen in AD

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T/F Spongiform diseases can also occur spontaneously, without known infectious process.

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T

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All prion proteins contain tracts of repeated ______ which appear to be essential for the conversion process.

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Gln-Asn residues

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T/F Proteins are resistant to nucleic acid degradating enzymes

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T

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Symptoms of Creutzfeld-Jakob disease (CJD)

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Loss of motor control, dementia, paralysis, wasting, eventually death usually following pneumonia

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Disease characterized by non-inflammatory lesions, vacuoles, amyloid protein deposits, astrogliosis. Characterized by severe selective atrophy of thalamus.

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Fatal familial insomnia (FFI)

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How is Gerstman Strausser Shinker disease (GSS) distinct from CJD?

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Occurs much less frequently. happens in 4th or 5th decade (CJD is older), characterized by cerebellar ataxia and motor problems. Dementia is less common.

Disease course is milder. Patient lives for several years.

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Prion diseases in infants

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Alpers Syndrome.

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2 ways humans can be affected by prions

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1) Acquired infection: thru diet or medical procedures.
2) Apparent autosomal dominant mendelian transmission

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T/F Prior disease have long incubation periods

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T

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immortalization/transformation of cells in culture: what may this be associated with in vivo?

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Oncogenic viruses in vivo

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Difference between immortalized and transformed cells.

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Immortalized: retain many normal characteristics but undergo unlimited cell divisions.

Transformed: lost most if not all other restrictions of cell type. Generally morphologically distinct from normal counterparts. Also immortal

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What proportion of human cancers are caused by viruses?

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20%

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T/F Immortal cells lack serum or growth factor dependencies

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F. This is descriptive of TRANSFORMED cells.

Front 39

Normal host genes that when mutation or altered in expression can lead to tumor formation

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proto-oncogenes

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Main mechanisms of viral oncogenesis

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1) Direct:
- expression of virally-transduced oncogenes
-modification of host proto-oncogenes

2) Indirect

- induction of continuously dividing cells

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acutely transforming retroviruses: mechanism of viral oncogenesis

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Contain a copy of an oncogene that was originally derived from a host cell proto-oncogene.

Contains mutations that can induce oncogenesis.
they're usually defective viruses and can't replicated without coinfection with a helper virus.

Result in rapid induction of tumors in animals.

Proteins encoded appear to be involved in signal transduction pathways that ultimately affect nuclear transcription factors and hence expression of genes that activate cell proliferation.

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Chronic transformation retroviruses:: mechanism of viral oncogenesis

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Do not encode oncogenes.

Autonomuos (able to replicate on their own.) Tumor development takes a long time and only happens in small %age of infected hosts.

Tumor cells are monoclonal

<b>Proviral insertion into proto-oncogenes results in activation of oncogene</b>

Front 43

Which of these transforms cells in culture?
A) Acute transformation retrovirus
B) Chronic transformation retrovirus

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A)

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T/F HIV has been shown to directly cause some cancers.

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F

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Only human retrovirus clearly implicated in causing cancer

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HTLV-1

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modified regulatory genes derived from the host (proto-oncogenes) vs. those from the virus. How are they named differently?

Back 46

Cell (host) derived: have a "C" in front.

Virus derived: Have a "V" in front.

C-myc; V-myc

Front 47

Which type of virus does this describe:

contain viral encoded oncogenes

efficiently transform cells in culture

often cause tumors in each infected animal

tumor development is generally rapid

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Acute transforming retrovirus

Front 48

Which type of virus does this describe:

- do not contain viral oncogenes

- do not transform cells in culture

- often only cause tumors in a small proportion
of infected animals

- may require an extensive “incubation” period

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Chronic transforming retrovirus

Front 49

Over half of all human cancers contain mutations in what?

Back 49

p53

Front 50

Most DNA viruses replicate where?

Back 50

Nucleus. They use host DNA synthesizing machinery

Front 51

Why is it necessary for DNA viruses to encode specific genes to enhance cell cycle progression/drive cells into S phase?

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The host cells aren't actively replicating and therefore lack the necessary nucleotides to make the virus enzymes.

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What are the two key cellular tumor suppressors that DNA viruses interfere with?

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p53, pRB

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pRB: normal function

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Binds a host transcription factor (E2F) and prevents it from activating a number of cellular promoters, thereby preventing cell cycle progression.

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p53: normal function

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Tumor suppressor that's up-regulated by DNA damage and stress.

Activates other genes that block cell cycle progression.

Can promote apoptosis when necessary.

VERY IMPORTANT in controlling tumor development.

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Associated with 70% of cancers of cervix

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HPV 16 and 18

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Mechanism of oncogenesis of HPV 16 and 18

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E7 protein from both of these strains inactivates pRB.

Front 57

Merkel cell polyoma virus : which cancer is it linked to?

Back 57

Merkel cell carcinoma: skin cancer

Front 58

Induction of continuously replicating cell populations is an example of what?

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Indirect oncogenic mechanisms of oncogenic DNA and RNA viruses

Front 59

Epstein-Barr virus is in the ____- family of herpes viruses, which contain a number of oncogenic viruses.

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&gamma;

Front 60

EBV is associated with what cancers?

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African Burkitt's lymphoma, Asian nasopharyngeal carcinoma, certain types of Hodgkin's and non-Hodkins lymphomas

Front 61

EBV infects ____ cells where it remains for life as a circular episome.

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B

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T/F EBV is integrated into host genome.

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F. It's maintained as a circular episome.

Front 63

How does African Burkitt's Lymphoma result frm EBV?

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All EBV-associated BL cells contain a chromosomal translocation that moves c-myc near the Ig enhancer.

The viral proten EBNA-1 is very weakly presented by class I molecules.

It's thought that EBV infection initially provides a continuous supply of proliferating B cells.

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Only protein from EBV expressed during latent infection

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EBNA-1

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What's special about EBNA-1?

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It's resistant to proteolytic processing, therefore is only very weakly presenting by Class I MHC.

Front 66

Human T lymphotrophic virus I
(HTLV-1): what cancer is it associated with?

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adult T-cell Leukemia (2-5% life-time risk)
HTLV-1 associated myelopathy (<1% life-time risk)

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Kaposi's Sarcoma-associated Herpes Virus (KSHV, HHV8): mechanism of oncogenesis

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Immortalization of B cells.

Tumors derive from lymphatic endothelium.

protein LANA functions like EBNA1 to maintain latent episome, but it <b>inactivates p53 and pRB.</b>

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Hep B and C are associated with what cancer?

Back 68

Hepatocellular carcinoma

Front 69

Mechanism of HBV and HCV oncogenesis --> hepatocellular carcinoma.

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Not clear. Tumors are often monoclonal and contain integrated HBV DNA that's highly deleted and rearranged. Some tumors lack detectable HBV DNA.

Maybe damage to liver tissue from chronic viral infection --> Continuous efforts to regenerate liver tissue, producing rapid cell proliferation. Potentiates the probability of accumulating cellular mutations necessary for oncogenesis.

Front 70

Inactivation of which cell cycle progression checkpoint protein is important for replication of many DNA viruses?

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p53

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components that optimize vaccine response to antigens

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adjuvants

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Basically determines how many things you're immunizing against (eg., number serotypes covered by a vaccine); increases range of efficacy of single vaccine

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valency

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vaccines made from inactivated toxic compounds that cause illness rather than the micro-organism

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Toxoid vaccines

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3 diseases for which toxoid vaccines are used

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Tetanus, Diphtheria, pertussis

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T/F Toxoid vaccines are generally delivered in combination

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T

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Mechanism for Toxoid vaccines

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T cell dependent

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4 diseases for which a killed/inactivated virus vaccine is available

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1) Hep A
2) Poliomyelitis
3) Japanese encephalitis
4) Influenza

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Schedule to get vaccines for toxiods

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Primary series in infancy, boosters regularly throughout adulthood

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Schedule to get killed/inactivated vaccines

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Primary series in infancy. May or may not need boosters. Flu must be given yearly.

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3 diseases for which polysaccharide vaccines are used

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1) Pneumococcal invasive disease
2) Meningococcal disease
3) Typhoid fever

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T/F Mechanism for polysaccharide vaccines is T cell independent

Back 81

T

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Conjugate vaccnies: why developed?

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To fill gap for peds diseases there were no vaccines for

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Conjugate vaccines: what are they?

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certain bacteria have polysaccharide outer coats that are poorly immunogenic. By linking these outer coats to proteins (e.g. toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.

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What are T-indept antigens?

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An antigen-specific antibody response can still occur if the antigen has a repetitive structure (i.e. polysaccharide) or is arranged in a repetitive manner (i.e. proteins arranged on a viral capsid) leading these to be called T-independent antigens.

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What are the implications that Young children have been shown to be unresponsive to T-independent antigens?

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They're particularly susceptible to infection by encapsulated bacteria and certain viral pathogens.

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3 Conjugate vaccines routinely given

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1) H influenzae B (HiB)
2) Pneumococcal conjugate vaccine
2) Meningococcal conjugate vaccine

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What are the live vaccines currently given?

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MMR; Varicella, Typhoid, Polio, Yellow Fever, Flu (nasal), Rotavirus

Front 88

Which vaccines are the protein/subunit type?

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HPV primary series.
Hep B primary series and post-exposure prophylaxis

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How to test for immunity?

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Generally, Antibody testing for assessment of vaccine receipt or measurement of efficacy

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Only type of T cell independent vaccine

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Those for polysaccharides

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Diseases for which a T cell indept vaccine exists

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Pneumococcal invasive disease
Meningococcal disease
Typhoid fever