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MIMM 324 > Papillomavirus > Flashcards

Papillomavirus Flashcards

1
Q

Does papillomaviruses have an envelope?

A

No

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2
Q

Describe papillomaviruses

A

Double stranded DNA
Icosahedral capsid

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3
Q

What family are papillomaviruses part of?

A

Papillomaviridae

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4
Q

Papillomaviruses are part of which Baltimore class?

A

Class I

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5
Q

What do papillomaviruses infect?

A

Keratinocytes within differentiating epithelia of skin and mucosa

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6
Q

What do papillomaviruses cause?

A

Hyper-proliferation benign and malignant lesions of the skin and mucosa

Notably cervical cancer in women

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7
Q

How is HPV defined?

A

Types: L1 ORF is more than 10% different than known types

Variant: less than 10%

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8
Q

What are the diseases caused by HPV?

A

Mucosal:
- Cervical and anogenital cancer
- Oropharyngeal cancer
- Genital warts
- Laryngeal papillomas

Cutaneous:
- Plantar warts
- Common warts
- Flat warts

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9
Q

What is EV?

A

Epidermodysplasia verruciformis
Rare genetic disease with a higher risk of developing skin carcinoma on sun-exposed skin

Abnormal susceptibility to HPV 5 and HPV 8, and other EV types

EV types are beta-HPVs that are present in the skin of most people without symptoms

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10
Q

What is the cause of EV?

A

Mutations in EVER1, EVER2, and CIB1 genes

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11
Q

Average length of HPV infection is…

A

8-12 months

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12
Q

What are the screening programs and treatments for HPV?

A

PAP test: detect abnormal keratinocytes
Molecular detection: viral nucleic acids, performed on PAP sample
Colposcopy: direct visualization of lesions, biopsies for histology
Treatments: physical ablation, cytotoxic agents, immunomodulation

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13
Q

What are prophylactic vaccines?

A

Virus-like particles made by expression of L1 in yeast or insect cells

Mixture of VLPs from prevalent HPV types

Provide high levels of antibodies and protection against cervical cancer and condylomas

Expected to protect against other HPV-associated cancers

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14
Q

Describe papillomavirus capsid.

A

One viral genome wrapped in his tones
Icosahedral symmetry with atypical T=7 arrangement
Made of 72 pentamers of L1, which interact through long tails for stability
- no hexamers
- 60 of the 72 L1 pentamers are surrounded by 6 neighbouring pentamers arranged along a 6-fold symmetry axis
- capsid is made of 360 subunits instead of 420
12 copies of minor capsid protein L2 are found in the inside of the capsid and may help with packaging the genome

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15
Q

80% of all cases of HPV-associated cancers are ___

A

Cervical cancers

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16
Q

The incidence of cervical cancer is inversely correlated with access to ____

A

Cervical screening programs

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17
Q

HPV replication cycle depends on ____

A

Differentiation of keratinocytes in stratified epithelia

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18
Q

HPV infects ______ but produces new visions in ____

A

Undifferentiated basal cells
Differentiated cells

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19
Q

How does HPV infect basal cells?

A

L1 binding to heparin surface proteoglycans triggers clathrin-dependent endocytosis

Genome is established as an episome in the nucleus and replicated by E1 and E2 to about 50-100 copies/nucleus

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20
Q

What does HPV do in differentiated cells?

A

Packaging and release of virions
Late gene/capsid protein expression
Genome amplification
- viral episodes are replicated by E1 and E2 to 1000 copies/nucleus
Oncogene-induced cell proliferation
- E7 forces differentiated cells to enter S-phase
- E6 prevents their death by apoptosis
- Cells express host DNA replication factors

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21
Q

Describe papillomavirus genome

A

8kbp double stranded DNA circle

Encodes less than 10 proteins

Three functional regions
- Early genes
- Late genes
- Regulatory region named LCR or URR
- LCR = Long control region
- URR = Upstream regulatory region

LCR/URR is the regulatory area for
- transcription
- DNA replication
- Segregation of the genome

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22
Q

What are the main proteins in HPV?

A

E1: DNA helicase, the only HPV enzyme
E2: Helicase loader, transcriptional repressor, segregation factor

E1 and E2 are in charge of viral DNA replication, gene expression, and segregation

E4: Disrupts cytokeratin network
E5: Recycles growth factor receptors

E4 and E5 are in charge of genome amplification

E6: Binds multiple targets including p53
E7: Binds multiple targets including pRb

E6 and E7 are viral oncogenes

L1: Major capsid protein
L2: Minor capsid protein

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23
Q

How does HPV transform a cell?

A

Telomerase activation
Inhibition of p53, pRb tumor suppressors = immortalization
Ras V12 activated oncogenes = transformation

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24
Q

What causes the immortalization of HPV?

A

HPV E6 and E7
Ad E1A and E1B
SV40 large T antigen

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25
Q

What is senescence?

A

When primary cells are put in culture in vitro, they only divide a limited number of times and eventually die because of the erosion of their telomeres

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26
Q

What is immortalization?

A

When primary keratinocytes are made to express the two HPV oncogenes E6 and E7, they become immortal and will divide indefinitely in cell culture

27
Q

What is transformation of a cell?

A

When immortalized cells acquire additional mutations, such as mutations that activate the Ras oncogene, they become transformed. Cells that are transformed have additional growth properties, including the capability of forming tumours in animals

28
Q

What kind of assay do you use to study HPV cycle in vitro?

A

Southern blot to examine viral DNA

Episomal shown in WT. Not shown in mutant genomes: mutations in viral genome that suppress DNA replication

29
Q

What is the difference between epithelial tissue that are normal and have HPV?

A

Epithelium is thicker, and cells still have their nucleus in everywhere

30
Q

True or false: Infection by high-risk HPV type is necessary but not sufficient for the development of cervical cancer

A

True

31
Q

During the normal viral life cycle, the HPV genome is maintained as …

A

Episomes

32
Q

In most high-grade lesions and cancers, the viral genome is found ___ into the host chromosomes

A

Integrated
Integration is a bio marker of cancer progression

33
Q

Integration of the HPV genome often results in ___

A

Disruption of the E2 gene

Because E2 normally represses transcription of the E6 and E7 oncogenes, disruption of E2 leads to higher expression of the E6 and E7 proteins

34
Q

HPV: Re-expression of E2 ____ E6 and E7 and ___ p53 and pRb pathways

A

Represses
Reactivates

Cells cease to proliferate and die by senescence/apoptosis

35
Q

Cervical carcinoma cells require continuous expression of ___ and ___

A

E6 and E7 are needed for growth and survival

36
Q

What is the role of E7

A

Induces cellular proliferation
Separates (inhibits) E2F and pRB complex

37
Q

What is the role of E6?

A

Prevents apoptosis that results from E7-induced proliferation
Inhibits p53

38
Q

How does E7 induce cellular proliferation? (S phase entry)

A

Degrades pRb (induce its degradation by the protease by binding to it)
Stimulates Cln-Cdk2
Inhibits Cln-Cdk inhibitors (p21, p27)
Activate E2F: phosphorylation of pRb (E2F separates from pRb)

39
Q

What is the structure of E7?

A

Small zinc-finger protein that contains a LxCxE Rb-binding motif

Structure of E7 LxCxE peptide bound to the pocket region of pRb. E7 peptide is an extended conformation

40
Q

How does E6 induce degradation of p53?

A

E6 forms a complex with E6AP (E6-Associated Protein), a cellular E3-ubiquitin ligase

The E6-E6AP complex binds to p53 and promotes its polyubiquitination

Poly-ubiquitinated p53 is targeted to and degraded by the proteasome

E6AP is not implicated in p53 degradation in normal cells but is usurped by HPV E6

41
Q

Describe the structure of E6 in HPV

A

Small protein with two zinc-fingers

E6AP peptide: E6 binds to an alpha-helical LxxLL motif in E6AP

The three leucines are on the same surface of the helix

42
Q

How does E6 prevent telomere erosion in HPV?

A

Activates telomerase

  • Ribonucleoprotein complex: TER RNA, TERT protein with reverse transcriptase activity
43
Q

HPV E6 ___ TERT expression at the transcriptional level

A

Increases

44
Q

HPV: genome replication is initiated at…

A

The viral origin (ori)

45
Q

Why is it hard for drugs to target HPV?

A

DNA helicase is the only viral enzyme; the other proteins have no enzymatic activity

46
Q

What is needed for DNA replication of HPV?

A

E1, E2, and host DNA replication machinery

47
Q

What is the role of E1 in HPV?

A

Bind to replication origin

Helicase activity

Interact with cellular replication factors

48
Q

HPV: The Ori contains 3 types of DNA elements:

A

E1 binding sites (E1BS)
E2 binding sites (E2BS)
An AT rich region

49
Q

How is DNA replication initiated in HPV?

A

Ori
Assembly of E1-E2-ori complex
Assembly of the E1 double-hexamers
Replication-competent complex

50
Q

How does the E1-E2-ori complex form?

A

E2 binds with high affinity and specificity to the origin. E2 also interacts with E1 to recruit it to the ori. E2 acts as a helicase loader

51
Q

How is the E1 double-hexamers in HPV formed?

A

The binding and hydrolysis of ATP by E1 promotes its assembly into double hexamer

Each E1 hexamer encircles a DNA strand

52
Q

HPV: How does the replication-competent complex work?

A

E1 unwinds DNA and interacts with host DNA replication factors like the ssDNA-binding protein RPA, polymerase alpha primase and topoisomerase I

53
Q

Where does the DNA and E1 bind to in E2?

A

DNA-binding domain (in E2) binds to E2BS in the ori
E1-binding domain (in E2, also called TAD, Transactivation domain) binds to the E1 helicase domain

54
Q

What are the functional domains of the E1 helicase?

A

N-terminal region: Contains motifs needed for E1 nuclear import and export

DNA binding domain (DBD): Binds to E1BS in the ori to facilitate assembly of double hexamer

HD (helicase domain):
- The enzymatic portion of the protein
- Has ATPase and DNA helicase/unwinding activity
- Sufficient for assembly into hexamers
- Interacts with E2 proteins and host DNA replication factors

55
Q

How is DNA unwinding in HPV?

A

E1 assembles as a hexamer around ssDNA

DNA unwinding is largely the consequence of E1 trans locating along ssDNA (E1 is a translocase)

Translocation involves conformational changes in E1 induced by ATP-binding and hydrolysis

Six ssDNA-binding hairpins (beta-hairpins) interact with ssDNA in the central channel and change conformation upon ATP-binding and hydrolysis

56
Q

HPV: Segregation of the viral genome is during…

A

Mitosis

57
Q

How does HPV ensure equal partitioning of viral episomes to daughter cells during mitosis?

A

E2 tethers the viral genome to mitotic chromosomes

58
Q

How does E2 tethers the viral genome to mitotic chromosomes?

A

By interacting with Brd4

59
Q

What is Brd4?

A

Bromodomain-containing protein 4 is a chromatin reader that binds acetylated nucleosides and remains associated with chromatin during mitosis

E2 TAD interacts with the C-terminal 20 amino acids of Brd4

60
Q

HPV viral gene transcription: Name the two promoters

A

Early gene transcription (pE) located in the LCR
Late gene transcription (pL) located in E6 gene. Activity of pL is dependent on keratinocyte differentiation

61
Q

What does the keratinocyte-specific enhancer do in HPV?

A

Located in LCR
regulates both early and late promoters

62
Q

How is viral gene transcription regulated in HPV?

A

Primarily by ubiquitous cellular transcription factors (AP1, SP1) that bind to the LCR

By E2 which functions as a repressor

63
Q

Early and late mRNAs in HPV are ____

A

Alternatively spliced and poly-cistronic

MIMM 324 (10 decks)

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