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MIMM 324 > Polyomaviruses > Flashcards

Polyomaviruses Flashcards

1
Q

What family is polyomaviruses part of?

A

Polyomaviridae

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2
Q

Do polyomaviruses have envelopes?

A

No

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3
Q

Describe the virion of polyomaviruses?

A

Non-enveloped, 40-45nm, icosahedral

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4
Q

Polyomaviruses: What direction in DNA replication?

A

Bidirectional from a. Unique origin of replication

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5
Q

How many proteins are encoded in polyomaviruses?

A

5-9 viral proteins

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6
Q

What is the host range for polyomaviruses?

A

Mammals, birds, fish

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7
Q

PyV: Early and late transcripts are encoded on ___ DNA strands

A

Opposite

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8
Q

What is the link between SV40 and the vaccine?

A

Early batches of polyomyelitis vaccine were contaminated with SV40

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9
Q

Does SV40 cause cancer in rodents, monkeys, and humans?

A

Monkeys: replicates in kidneys without disease
Rodents: cancer in laboratory conditions
Humans: SV40 found in some cancers but no clear evidence of causal relationship

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10
Q

True or false: SV40 can be lytic and lysogenic

A

True

Infection in permissive cells: new virions and cell lysis
Abortive infection in non-permissive cells: result in transformation of cells

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11
Q

SV40: What is needed for cells to transform?

A

Expression of LTAg and STAg

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12
Q

What are the two PyVs identified?

A

BKPyV and JcPyV

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13
Q

How do BKPyV and JCPyV affect healthy children?

A

Primary infection
Causing mild illness
Through oral route

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14
Q

Describe latent infection of BKPyV and JCPyV and location

A

Establish life-long latency in immune privileged sites like the proximal renal tubes. 80-90% of people persistently infected

No disease during latency

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15
Q

When do JCPyV and BKPyV reactivate

A

Upon immunosuppression

Leads to productive lytic replication

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16
Q

BKPyV reactivating in common in …

A

Kidney transplant patients

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17
Q

BKPyV: lytic viral replication can result in …

A

Acute kidney injury, PVAN, and allograft loss

Haemorrhagic cystitis in bone marrow transplant patients

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18
Q

What is PVAN?

A

Polyomavirus-associated nephropathy

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19
Q

What are early symptoms of BKPyV?

A

Appearance of virus in urine (viruria) and blood (viremia)

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20
Q

What is the only treatment for PVAN?

A

Reduction of immunosuppression

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21
Q

What is a clear sign of BKPyV?

A

Immunohistochemical detection of LTAg

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22
Q

What is PML?

A

Progressive multi focal leukoencephalopathy

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23
Q

PML is caused by …

A

JCPyV

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24
Q

What is PML?

A

Demyelination disease of the CNS
Leads to progressive destruction of the white matter of the brain

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25
Q

PML is seen in…

A

AIDS patients, and multiple sclerosis patients treated with natalizumab (anti-integrin mAb drug)

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26
Q

How does JCPyV reach the brain?

A

Infecting B cells (leukocytes)

27
Q

Productive replication of JCPyV in ____, the myelinated cells of the CNS, leads to their ____ and to _____

A

Oligodendrocytes

Lysis

PML

28
Q

The JCPyV ___ is rearranged in PML, by deletions/duplication of DNA sequence blocks. The non-rearranged JCPyV is known as ____ and the rearranged ones as ____

A

NCRR
Archetype
Prototype

29
Q

What are the four PyVs associated with cancer?

A

BKPyV, JCPyV, MCPyV, TSPyV

30
Q

What is the only PyV identified as a human carcinogen?

A

MCPyV

31
Q

What is MCC?

A

Merkel cell carcinoma
Rare and aggressive skin cancer
80% cases caused by MCPyV

32
Q

What are Merkel cells?

A

Neuroendocrine cells at the base of the epidermis
Close to nerve endings and sense light touch

33
Q

What are the two aberrant events that contribute to MCC?

A

Integration of viral genome into host DNA
Truncation/mutations in LTAg that impairs its DNA replication activity but keeps its transforming activity

34
Q

What does LTAg do in MCPyV?

A

Inhibits pRb
Cooperates with STAg to transform Merkel cells into MCC cells

35
Q

___ transcribes polyomavirus genome?

A

Host RNA pol II

36
Q

What does the early region of the polyomavirus encode?

A

Alternatively spliced LTAg and STAg

37
Q

What does the late region of the polyomavirus genome encode for?

A

Capsid proteins VP1, VP2, and VP3

38
Q

The non-coding regulatory/control region (NCRR or NCCR) in a polyomavirus contains…

A

Early and late promoters
The origin of viral DNA replication (ori)

39
Q

How do we determine a new species of polyomavirus?

A

LTAg sequence differs by more than 15% to known species

40
Q

How many genera and species are there in polyomaviruses?

A

More than 100 species
6 genera (alpha, beta, delta, gamma, zeta)

41
Q

SV40 is part of which genus and species?

A

Beta
Macaca mulatta polyomavirus 1

42
Q

What genus is species does MPyV belong to?

A

Alpha
Mus musculus polyomavirus 1

43
Q

BKPyV is part of which genus and species?

A

Beta
Human polyomavirus 1

44
Q

What is LTAg in polyomavirus?

A

Oncogene
Involved in cellular proliferation (entry in S phase) and transformation

Hexamer is DNA helicase needed for viral DNA replication

Transcription factor that regulates the switch from early to late gene transcription

45
Q

How does LTAg promote cellular proliferation and transformation?

A

Interacting with host proteins
- Hsc70 chaperone via the J-domain
-pRb and related family members p107 and p130, via the LxCxE motif. These interactions release active E2F to promote S-phase entry
-p53, via the helicase/p53-binding domain. Prevents apoptosis

46
Q

What is the domain structure of SV40 LTAg?

A

JD: J-domain: binds to host HSc70 chaperone and stimulates its activity

LxCxE/pRb: Rb-binding motif. Binds host pRb, p107 and p130

NLS: Nuclear localization signal: interacts with host importing

OBD: Origin-binding domain. Binds to sites in the origin of DNA replication

Helicase/p53: Domain with DNA helicase activity and domain that binds to host p53

HR: Host range region

47
Q

What is needed for the transformation activity of LTAg?

A

N-terminal region: JD, LxCxE/Rb-binding motif
Sometimes p-53 binding domain needed

48
Q

The only viral protein required for genome replication in PyV is…

A

LTAg

49
Q

Describe the structure and function of STAg.

A

Shares an N-terminal J-domain with LTAg (overlapping coding sequence)
Helps LTAg, can’t transform cells by itself except for in MCPyV
Activates expression of genes needed for S phase entry and progression.

Activity of STAg depends on its interaction with host phosphatase PP2A.
Active form of PP2A consists of a heterotrimer
STAg replaces the substrate-targeting B subunit, inactivating the enzyme

50
Q

Describe icosahedral symmetry of PyV

A

T=7 icosahedral symmetry
72 pentamers of VP1 (12 pentamers with 5 neighbours, 60 pentamers with 6 neighbours)

51
Q

Important: PyV: Pentamers interact via the C-terminal portion of VP1 and are further stabilized by ….

A

Pentamers interact via the C-terminal portion of VP1 and are further stabilized by calcium ions and disulfide bonds between them

52
Q

SV40 entry: SV40 binds to ____ which triggers _____. SV40 moves to ____ and is targeted to the _____. Then enters into the _____ and then moves to _____. Genome is released for transcription and translation

A

GM1 gangliosides
Caveolae-dependent endocytosis
Endosomes
ER
Cytosol
Nucleus

53
Q

What are the attachment factors commonly used by polyomaviruses?

A

All PyV use sialic acid-containing receptors for attachment

Glycosaminoglycans
Integrity
Gangliosides

54
Q

What are sialic acid-containing receptors?

A

Glycoproteins or glycolipids with attached mono or oligosaccharides and terminal sialic residues

55
Q

What are glycosaminoglycans?

A

Contain repeating disaccharides and are attached to the polysaccharide sugar core by link proteins

56
Q

What are integrins?

A

Heterodimeric proteins comprised of alpha and beta chains
Contain beta propeller domain, thigh and calf domain, and epidermal growth factor binding domains

57
Q

What are gangliosides?

A

Glycosphingolipids with ceramide embedded in the membrane and an oligosaccharide chain with one or more sialic acids

May also contain a terminal sialic acid

58
Q

____ is the only PyV that uses clathrin-mediated endocytosis

A

JCPyV

59
Q

SV40, MPyV, and MCPyV use ____ endocytosis and or ____ to enter the cell. JCPyV and BKPyV may also use ____ to enter cells.

A

Caveolin-mediated endocytosis
Non-clathrin/non-caveolin lipid raft uptake mechanisms

Extracellular vesicles

60
Q

What attaches to the ganglioside receptor for PyV?

A

VP1

61
Q

PyV vesicle translocates to the ER through…

A

Microtubules

62
Q

In the ER, the PyV virion’s capsid structure is destabilized by…

A

Host disulfide isomerases

63
Q

In the cytoplasm, the PyV virion loses VP1 due to…

A

Low calcium conditions of the cytosol

MIMM 324 (10 decks)

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