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Biology of Cancer > Epstein Barr virus and cancer > Flashcards

Epstein Barr virus and cancer Flashcards

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1
Q

What are the 3 classifications of the herpesvirus?

A
  • alpha subfamily = herpes simplex 1 and 2 (HHV1/2) - associated w/ carcinoma of the resp. tract
  • beta subfamily = cytomegalovirus (HHV5) associated with Kaposi’s sarcoma
  • gamma family = EBV HH4 - associated with burkitts lymphoma and nasopharyngeal carcinoma
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2
Q

What are the characteristics of EBV?

A
  • EBV is a member of the gamma herpesvirus family
  • genome is 172kb linear double molecule which ciruculizes infected cells
  • EBV infects the B cells and certain epithelial cells
  • in culture EBV efficiently immortalises resting b cells
  • EBV associated diseases. = infectious mononucleosis, burkitts lymphoma, Hodgkin lymphoma
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3
Q

When does EBV infect B cells?

A
  • via the CD21 receptor found on B lymphocytes
  • two regions of homology exist between the receptor and EBV, allowing binding and internalisation
  • can only infect B lymphocytes at certain times during their growth and maturation
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4
Q

How does EBV enter the cells?

A

Epithelial cells - initial entry is via viral protein BMRF-1 that interacts with cellular beta-1 integrins
- followed by interaction of viral protein gH/gL with cellular integrins that triggers fusion of the viral envelope with the epithelial cell membrane
B lymphocytes - entrer via viral glycoprotein gp350, binds to cellular receptor CD21
- triggers fusion of the viral envelope with cell membrane, allowing entry
- human CD35 (CR1) is an additional attachment factor for gp350, and can provide a route for entry of EBV into CD21 - negative cells
- once EBV enters the cell, the viral capsid dissolved and the viral genome is transported to the cell nucleus

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5
Q

Describe lytic infection

A
  • primary infection is usually asymptomatic in childhood
  • virus is secreted in the saliva and human infection occurs through oral transmission - associated with infectious mononucleosis
  • by age of 40 = nearly everyone is infected
  • oropharyngeal infection = lytic infection where 80 viral genes may be expressed
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6
Q

Describe latent/persistant infection

A
  • lytic infection is followed by infection of circulating b cells
  • this leads to persistance of viral DNA in the nucleus, establishing a latent infection and a restrictive pattern of gene expression
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7
Q

How is lytic EBV treated?

A
  • during lytic cycle replication is via viral DNA polymerase
  • acyclovir is a guanosine analogue
  • it is phosphorylated by viral kinases only expressed during the lytic cycle
  • host cell kinases that convert it to acyclovir triphosphate, this then terminates DNA synthesis
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8
Q

Can latent EBV be treated with Acyclovir?

A

No
- does not generate viral kinases that activate the drug
insensitive to acyclovir

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9
Q

Where are the EBV particles found during lytic/primary infection?

A
  • primary site of lytic replication in oropharynx, cells that evade T-cell response establish stable reservoir
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10
Q

Where are the EBV particles found during latent/persistant infection?

A
  • persistant reservoir maybe recruited to germinal centres, re enter reservoir or differentiate into plasma cells and reactivate lytic cycle
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11
Q

How do we know what the latent genes are?

A
  • in vitro = peripheral blood lymphocytes from EBV infected individuals are placed in culture, the few EBV infected B cells give rise to spontaneous out growth of EBV-transformed cell line known as lymphoblastoid cell lines (LCL)
  • LCL can be generated by infecting resting b cells with EBV = valuable tool for research
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12
Q

What do LCLs express?

A
  • 6 EBV nuclear antigens (EBNAs - 1, 2, 3A, 3B, 3C and -LP)
  • 3 latent membrane proteins (LMPs 1, 2A, 2B)
  • transcripts from the BamHI region (BART transcripts)
  • 2 small, non-polyadenylated RNAs (EBER1 and EBER2)
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13
Q

What are the different types of latency?

A
  • in epithelial cells only latency II
  • Latency III usually found in naive B cells - enter germinal centre and proliferate, expanding pool of EBV cells
  • Latency II = GC infected cells = then differentiate into memory B cells, some of these show Latency I gene expression
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14
Q

What is the function of EBNA-1

A
  • expressed in all EBV-infected cells
  • found in nucleus, role in maintenance of the genome by binding to the origin of replication
  • not recognised by cytotoxic T cells
  • Gly-Ala repeat sequences are thought to prevent proteosomal degradation of EBNA-1
  • shown to inc. survival of infected B cells. Lowers p53 levels by binding to p53-regulatory protein, USP7 = ubiquitin specific protease that is key regulator of p53 and mdm2
  • may provide target for further therapy
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15
Q

What is the function of EBNA-2?

A
  • found in nucleus= transcriptional regulator and activator of several viral and cellular genes, such as LMP-1, LMP2 and CD23
  • interacts with DNA-binding protein to activate CD23 and LMP proteins
  • RBP-Jk is a downstream regulator of notch signalling pathway
  • deletion of EBNA2 = inability to transform b lymphocytes
  • phosphorylation of EBNA2 = suppresses activity
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16
Q

What is the function of EBNA3

A
  • related to proteins EBNA - 3A, 3B and 3C - expressed only in latency III
  • EBNA-2 are restricted to nucleus and function as transcriptional regulators
  • 3A and 3C essential for b cell transformation in vitro - EBNA3B is dispensable
  • 3C can upregulate CD21 and LMP1
  • EBNA3 proteins associate with RBP-PK transcription factor
17
Q

What are LMP1 and 2?

A
  • LMP-1 = found in membrane, considered the man transforming protein of EBV, major effector of virus induced cellular changed = inhibits apoptosis by activating NFkappaB
  • LMP-2- intrinsic membrane protein that prevents EBV infected cells from entry into the lytic cycle
18
Q

What are EBER-1/2?

A
  • Non polyadenylated RNAs that are essential for EBV transformation of B cells, can induce IL-10 which might suppress cytotoxic T cells
19
Q

Describe endemic Burkitts lymphoma

A
  • BL is a high grade lymphoma and needs urgent treatment. Affects children from age 2-16
  • tumour doubles in mass every 24 h and is fatal
  • treatment with cyclophosphamide (helps to induce apoptosis) = one dose can usually shrink tumour
20
Q

What are the 3 types of BL?

A
  • endemic - children and young adults in africa and new guinea
  • sporadic -children and adults outside endemic area
  • immunodeficiency-related - primarily associated with HIV infection
  • most BL exhibit type I Latency
21
Q

Pathogenesis of BL

A
  • all BL cases carry one of three characteristic chromosomal translocations that place the MYC gene under regulation of the lg heavy chain
  • many tumours also have mutation in the p53-ARF pathway.
  • BL is associated with either malarial or HIV infections
  • EBV may have an initiator role, providing pool of infected b-cells = risk of c-myc translocation
22
Q

Describe nasopharyngeal carcinoma

A
  • rare tumour arising from epithelium of nasopharynx
  • common in certain regions of east asia and africa = dietary and genetic factors
  • dietary risk factors - consumption of salt-cured fish high in nitrosamines and smoked food may play role
  • other factors = smoking and alcohol consumption
23
Q

What do NPC tumours look like?

A
  • blood stained postnatal discharge, impaired hearing, tinnitus
  • tumour presents in 3 forms :
  • proliferative - growth causing nasal obstruction
  • ulcerative - causing epistaxis
  • infiltrative - which causes cranial nerve involvement
24
Q

How are NPC tumours treated?

A
  • external beam radiotherapy - primary mode of therapy

- chemotherapy can be delivered together with radiotherapy and can include : cisplatin, 5-fluorouracil

25
Q

Evidence that LMP is involved in NPC

A
  • LMP1 is key EBV-encoded protein required for b cell immortalisation
  • In NPC - LMP1 behaves as oncogene
  • in human epithelial cells it exerts a variety of growth-promoting effects and potentiated anchorage-independent growth - greatly enhances cell motility and invasion - upregulate anti-apoptotic EGFR
26
Q

What is the structure of LMP1

A
  • 66kDa integral membrane protein = short amino acid cytoplasmic n-terminus, 6 hydrophobic alpha helical transmembrane spanning regions and cytoplasmic c-terminal tail
  • long c terminus which contains essential activating domain (CTAR)
27
Q

What is the role of bcl2 and p53 in NPC?

A
  • 90% of NPC tumours contain wt p53 genes
  • in the 10% of tumours that have mut p53, LMP1 may provide growth advantage
  • in 90% of NPC tumours LMP1 can modulate p53 activity
  • LMP1 stimulated expression of mdm2 = promotes p53 turnover
  • also repressed p53 mediated DNA repair
  • LMP1 can also synergise with Bcl-2 to override the growth suppression induced by wtp53
28
Q

What does EBER-1 bind to?

A
  • PKR is induced by interferons
  • 68kDa kinase, activity is enhanced by viral infection and cell stress
  • active PKR phosphorylated the ser 51 residue on the alpha subunit of eIF2alpha = inhibition of protein synthesis
  • activated by dsRNA
29
Q

What is the structure of PKR?

A
  • 2 double stranded binding motifs at n terminus = regulatory domain
  • c terminus = kinase domain
  • normally in cytoplasm PKR is found in inactive state
30
Q

How is PKR activated?

A
  • during viral infection, transcription leads to production of dsRNA
  • these activate PKR as part of antiviral mechanisms
  • dimerisation occurs = autophosphorylation
31
Q

How does EBER-1 play a role in PKR activation?

A
  • EBER-1 competes with PKR-activating dsRNA to prevent this inhibition of protein synthesis
  • activity is inhibited
32
Q

What is the function of EBER-1 in vivo?

A
  • expression of EBER-1 in EBV negative cells protects against IFN-induced apoptosis
  • EBER expression stimulated growth factors such as IL-9 and IL-10

Biology of Cancer (34 decks)

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