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MIMM 324 > 12. Polyomavirus > Flashcards

12. Polyomavirus Flashcards

1
Q

what family are polyomaviruses in?

A

polyomaviridae

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2
Q

why are polyomaviruses called polyomaviruses?

A

poly = multiple tumours

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3
Q

what is an example of polyomavirus?

A

Simian virus 40 (SV40)

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4
Q

3 characteristics of polyomavirus capsid

A
  1. non-enveloped
  2. 40-45nm
  3. icosahedral
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5
Q

describe the genome of polyomavirus

A

5 kbp circular dsDNA wrapped in histones

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6
Q

what baltimore class are polyomavirus?

A

Baltimore Class I

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7
Q

how are early and late transcripts of polyomaviruses encoded

A

early and late transcripts encoded on opposite DNA strand

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8
Q

how many viral proteins are there?

A

5-9

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9
Q

what are 3 types of hosts for polyomaviruses?

A
  1. mammals
  2. birds
  3. fish
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10
Q

describe SV40 contamination

A

SV40 was found to contaminate the poliovirus vaccine due to the monkey cells used to make the vaccine

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11
Q

how does SV40 affect monkeys, rodents, and humans?

A

MONKEYS - replicates without causing disease
RODENTS - causes cancer in laboratory conditions
HUMANS - no evidence for causing cancer

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12
Q

what happens when SV40 infects permissive cells?

A

virus goes thru full life cycle –> leads to lysis

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13
Q

what happens when SV40 infects non-permissive cells?

A

results in transformation/integration of DNA –> cancer

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14
Q

how do the early events differ when the virus infects non-permissive cells?

A

the early events of virus infection occur normally, until T antigens are expressed and trigger S-phase entry

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15
Q

what does integration of the viral genome cause?

A

leads to transformation of some cells –> only some bc integration is a rare event

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16
Q

which 2 proteins are generally needed for transformation?

A

LTAg and STAg

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17
Q

what were the first 2 polyomaviruses identified?

A

JC and BK

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18
Q

describe JC and BK infections (3 stages)

A
  1. primary infection in childhood (minor illness)
  2. latent infection thru life (no disease)
  3. reactivation with immunosuppression
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19
Q

what percent of people are persistently infected with JC/BK?

A

80-90%

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20
Q

What happens when the virus reactivates with immunosuppression?

A

causes lytic replication (massive replication) and serious disease –> often with mutations in genome that favours replication

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21
Q

what kind of people is BK virus common in?

A

common in kidney transplant patients

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22
Q

what can lytic viral replication of BK lead to? (3)

A
  1. kidney injury
  2. polyomavirus-associated nephropathy (PVAN)
  3. allograft loss
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23
Q

what are 2 early symptoms of PVAN?

A

VIRURIA –> virus in urine
VIREMIA –> virus in blood

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24
Q

what can BK virus cause in bone marrow transplant patients?

A

haemorrhagic cystitis

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25
what is the treatment for PVAN?
no antiviral drug --> reduce immunosuppression
26
what are the decoy cells we see in urine of BK patient?
virally infected epithelial cells with intranuclear viral inclusion bodies that resemble cancer cells
27
what disease does JC virus cause?
progressive multifocal leukoencephalopathy (PML)
28
what 2 types of people is PML found in?
1. AIDS patients 2. MS patients treated with natalizumab (anti-integrin mAb)
29
describe the 4 steps of PML
1. JC virus infects B cells 2. JC virus reaches the brain and replicates in oligodendrocytes 3. Oligodendrocytes lyse and become unable to myelinate neurons 4. JC non-coding regulatory region is rearranged to allow viral replication in the brain (brain tropism)
30
what are the diff names for JC virus genome when it is normal and rearranged
non-rearranged = archetype rearranged = prototype
31
what are the 4 polyomaviruses associated with cancer?
1. BK 2. JC 3. MC 4. TS
32
what is the only polyomavirus that is actually a human carcinogen?
merkel cell polyomavirus
33
what is merkel cell carcinoma? what % of cases are caused by merkel cell polyomavirus
aggressive but rare type of skin cancer that affects merkel cells 80% caused by merkel cell polyomavirus
34
what are merkel cells/
neuroendocrine cells at the base of the epidermis that are close to nerve endings and allow us to sense light touch
35
what are the 2 aberrant events of MC polyomavirus that contribute to MC carcinoma?
1. viral genome integrates into host DNA 2. truncations/mutations in LTAg that impairs its DNA replication activity but maintains its transforming activity
36
what does truncated LTAg do in merkel cell polyomavirus
truncated so viral replication genes are not present --> by inhibiting Rb will work with STAg to transform merkel cells into MC carcinoma
37
where is the polyomavirus genome processed? --> what does this mean?
in the cell's nucleus --> so it is wrapped in histones
38
what is the polyomavirus genome transcribed by?
RNA pol II
39
what are the 2 transcriptional units of polyomavirus genome?
1. EARLY 2. LATE
40
what does the early region encode?
early region encodes the alternatively spliced LTAg and STAg
41
what does the late region encode?
VP1, VP2, VP3
42
what is the third region of the genome called? what does it contain (2)
called Non-Coding Regulatory/Control Region (NCRR/NCCR) has early/late promoters and origin of viral DNA replication
43
how are polyomaviruses classified? how can a new polyomavirus be assigned to a new species?
based on amino acid sequence of viral LTAg if LTAg sequence differs by >15%, it is a new species
44
how many species are there? how many genera are there?
>100 species in 6 genera
45
which 3 genera contain viruses that infect mammals, including humans
alpha, beta, delta
46
what are the 3 roles of LTAg? what do these functions rely on?
1. oncogene 2. hexameric DNA helicase 3. transcription factor rely on interaction of LTAg with host proteins
47
what is the oncogene function of LTAg involved in? (2)
1. cellular proliferation (via entry in S-phase) 2. transformation
48
what is the hexameric DNA helicase function of LTAg involved in?
DNA replication
49
what is the transcription factor function of LTAg involved in?
regulates switch from early to late gene transcription
50
what are 3 host proteins that LTAg interacts with?
1. Hsc70 chaperone 2. pRB 3. p53
51
how does LTAg interact with Hsc70 and what does it lead to?
J-domain of LTAg binds Hsc70 to remodel the pRb-E2F complex to help release pRb from E2F
52
how does LTAg interact with Rb and what does it lead to?
Rb interacts with LxCxE Rb-binding motif to cause E2F to be released from Rb to promote S-phase entry for proliferation
53
how does LTAg interact with p53 and what does it lead to?
binds at helicase/p53 domain to block apoptosis
54
what are the 6 domains of LTAg and their roles?
1. J-domain binds Hsc70 2. LxCxE binds Rb and family members p107 and p130 3. nuclear localization signal binds host importins 4. origin binding domain binds ori 5. helicase/p53 binds p53 and has DNA helicase activity 6. host range region for viral replication incertain cell types
55
which domains of LTAg are required for DNA replication activity?
J-domain, NLS, OBD, and helicase domains (most of the protein)
56
which domains of LTAg are required for transformation activity?
mainly N-terminal region: JD and LxCxE/Rb domain and sometimes p53-binding domain
57
which viral proteins are required for genome replication?
only LTAg! everything else from host
58
3 functions of LTAg during REPLICATION
1. finds origin of DNA replication by itself and binds origin in NCRR to initiate DNA synthesis 2. LTAg assembles into double hexamer with helicase activity to unwind the DNA 3. interacts with host DNA replication factors
59
how is viral DNA replication promoted?
LTAg drives the cells into S phase to promote synthesis of host replication machinery
60
what does STAg share with LTAg?
STAg shares an N-terminal J-domain with LTAg via overlapping coding sequence
61
is STAg essential?
not essential but can help improve viral proliferation in most polyomaviruses
62
2 roles of STAg
1. activates expression of genes needed for S phase entry via enhancing LTAg activity 2. in most viruses, STAg cannot transform cells on its own but increases transformation efficiency of LTAg
63
why is STAg of MC polyomavirus special?
STAg is the dominant oncogene for MC polyomavirus
64
what does the activity of STAg depend on?
depends on its interaction with host phosphatase PP2A
65
how does STAg interact with PP2A?
PP2A is a heterotrimer and STAg replaces the substrate-targeting subunit (that normally gives specificity to certain substrates) and inactivates the enzyme i.e. STAg inhibits PP2A
66
describe the icosahedral symmetry of polyomavirus capsid
T=7 arrangement --> 72 pentamers of VP1 12 pentamers surrounded by 5 neighbours 60 pentamers surrounded by 6 neighbours
67
how do pentamers interact w each other and how are they stabilized?
pentamers interact via C-terminal portion of VP2 pentamers stabilized by Ca2+ ions and disulfide bonds
68
what do VP2 and VP3 and the N-terminus of VP1 interact with?
associate with pacakged genome
69
5 steps of SV40 entry into cell:
1. SV40 binds GM1 gangliosides as entry receptors 2. caveolae-dependent endocytosis targets virus to endosomes 3. from endosomes, SV40 is targeted to ER 4. SV40 leaves ER to cytosol 5. from cytosol, enters nucleus and genome is released
70
what kind of receptors do polyomaviruses use for attachment?
all contain sialic acid-containing receptors for attachment
71
which entry mechanism does JC virus use?
clathrin-mediated endocytosis
72
which entry mechanism do SV40, BK, m, and MC use?
caveolin-mediated endocytosis and/or non-clathrin/non-caveolin lipid raft uptake mechanisms
73
what is special about JC and BK virus entry?
JC and BK may use extracellular vesicles for entry, bypassing the need for cellular attachment and entry factors
74
overall polyomavirus life cycle: (10 steps)
1. VP1 attaches to cell and enters via diff receptors and entry mechanisms 2. vesicle translocates along microtubules to reach ER 3. in ER, host disulfide isomerases destabilize capsid structure 4. then exported to cytoplasm with low Ca2+ which trigger loss of VP1 (uncoating) 5. viral genome imported into nucleus and maintained as episome 6. transcription of early genes 7. expression of T antigen triggers cell to enter S-phase and promotes LTAg-dependent replication of viral DNA in nucleus 8. transcription of late genes (capsid) 9. new virions assembled 10. virions released by lysis

MIMM 324 (37 decks)

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