Slow Viruses & Prions

Question 0

Human Polyomaviruses

Answer 0

• Small, non-enveloped, circular DNA viruses
• Genomes are “minichromosomes”
• Genomes may replicate episomally
-may integrate into host cell chromosome
• Discovered as animal tumor virus (SV40) contaminating vaccines
• Used as models for study of oncogenic transformation
• 10 known human viruses, mostly recent
• Ubiquitous, life long infections
• Pathologic significance mostly unknown
– Three are known causes of disease
– Oncogenicity suspected, known in case of MCPV
– Disease of brain in JC Virus-PML; GU tract in BK virus
– “Slow” infection important for disease progression

Question 1

Define Slow Viruses

Answer 1

• Viral infections w/ persistent, latent, or relapsing courses
• resulting in disease manifestations developing years after onset

Question 2

Merkel Cell Cancer

Answer 2

• Highly aggressive skin cancer of elderly
• 3X Increase incidence in US over 10 yr
• Neurectodermal tumor
• More common in immunosuppressed
(similar to Kaposi’s Sarcoma)
• Pathogenesis:
-Childhood MCV Infection; Persistence
-Immunosuppression, Viral Reactivation
-Exposure to Sun or other mutagens
-Replication Defective Virus; Integration
-Viral Oncogene Expression
-Leads to Merkel Cell Cancer

Question 3

JC Virus

Answer 3

• Infection:
– Common, asymptomatic infection of late childhood
– Persists in kidney epithelium, lymphocytes, and bone marrow
*found in brain
• Disease: Progressive Multifocal Leukoencephalopathy (PML)
– Focal demyelinated plaques in white matter surrounded by infected oligodendrogliocytes
– Immune deficient, AIDS; associated gliomas
• Treatment: HAART

Question 4

BK Virus

Answer 4

-Infection:
   • Childhood, asypmptomatic 
   • Kidney epithelium, lymphocytes
-Disease:
   • Tubular interestitial nephritis, Hemorrhagic cystitits 
   • Renal and bone marrow transplantation
-Treatment:
   • Decrease immunosuppression 
   • Antivirals

Question 5

Transmissible Spongiform Encephalopathies

Answer 5

• Disease: encephalopathy w/ dementia, cerebellar abnormalities
• Pathology: Spongiform Changes +/- amyloid plaques
• Etiology: Caused by filterable agent, varied transmission
-Kuru
-Creutzfeld-Jacob Disease
-Familial Neurologic Syndromes (PrP gene mutations)

Question 6

Iatrogenic Spongiform Encephalopathies

Answer 6

• Human pituitary growth hormone epidemic
• Corneal transplants
• Dura mater transplants
• Stereotactic electrodes

Question 7

New Variant CJD

Answer 7

• Neuropsychiatric disease presenting in adolescence and young adulthood (~20-30y/o), transmitted mostly to <15 y/o
• Progresses to dementia
• Associated with dense amyloid deposits
• Associated with specific, homozygous PrP genotype
• Associated w/ transmissible agent that causes amyloid disease in mice

Question 8

Pruisner’s Prion Hypothesis

Answer 8

• Current accepted model for cause of TSE
• Was called infectious amyloid
• Protease resistant Prion protein (PrP-Res) forms amyloid
-infectious agent
• Deposition of abnormal protein:
-recruits normal PrP-C to associate and fold abnormally
-forms amyloid (nucleation)
• Explains:
– infectious nature of acquired & inherited forms
– non-viral characteristics

Question 9

Circular DNA Virus Theory

Answer 9

• characteristics similar to small circular DNA viruses
-size & density
-1000-4000 kb genome
• Different TSE agents have different heritable properties
• DNA present in purified infectious PrP-Res
• Digestion of PrP-Res & loss of infectivity of TSE agent can be achieved separately
• Resistance to nuclease digestion can be related to affinity for nuclear binding proteins

Question 10

Small Circular DNA Viruses in Humans

Answer 10

• Polyomaviruses 
• Hepatitis B virus 
• Hepatitis Delta virus 
• Anelloviruses of Circoviridae family: 
– Torque Tenoviruses (TTV): 5 groups 
– Torque Teno Minivirus (TTMV)