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Biology of Cancer > Epstein-Barr virus and Cancer > Flashcards

Epstein-Barr virus and Cancer Flashcards

1
Q

What is Epstein-Barr virus (EBV)?

A

The fourth human herpesvirus (HHV4)

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2
Q

How was EBV discovered?

A
  • in 1958 Burkitt found lymphoma in children that as derived from viral particles discovered by Epstein and Barr
  • It was similar structurally to other HHVs but has distinct biological activities
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3
Q

What are the 3 subfamilies of HHV?

A
  • alpha = HHV1/2, respiratory carcinomas
  • beta = HHV5, Kaposi’s sarcoma
  • gamma = EBV, Burkitt’s lymphoma/nasopharyngeal carcinoma
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4
Q

What are some characteristics of EBV?

A
  • member of the gamma subfamily of HHVs
  • genome is a 172kb linear ds molecule that circulates in infected cells
  • infects B cells and other certain epithelial cells
  • efficiently immortalises resting B cells
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5
Q

What are diseases associated with EBV?

A
  • infectious mononucleosis (mono)
  • Burkitt’s lymphoma
  • nasopharyngeal carcinoma
  • Hodgkin’s disease
  • B cell lymphoma in immunocompromised hosts
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6
Q

How does EBV infect B cells?

A
  • infect via the viral glycoprotein gp350 which binds to the CD21 receptor found on B cells
  • 2 regions of homology exist between the receptor and EBV which allows binding of the viral envelope and cell membrane
  • EBV enters the B cell and the viral capsid dissolves to allow the viral genome to be transported to the nucleus
  • can only infect B cells at certain times during their growth and maturation
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7
Q

How does EBV infect epithelial cells?

A
  • infect via viral protein BMRF-1 which binds to the cellular b1 integrins of the cell
  • the viral protein gH/gL also binds with the integrins which triggers fusion of the viral envelope with the cell membrane
  • EBV enters the B cell and the viral capsid dissolves to allow the viral genome to be transported to the nucleus
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8
Q

How does EBV transmit?

A
  • primary infection is usually asymptomatic in childhood
  • virus is secreted in the saliva and is transmitted orally
  • by the age of 40, almost ever everyone is infected
  • could produce a lytic infection where <80 genes may be expressed
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9
Q

How does EBV work latently?

A
  • the initial lytic infection is followed by infected circulation of B cells
  • results in persistent viral DNA in nucleus which establishes a latent infection
  • latency depends on the differentiation stage of the cell
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10
Q

How does EBV go from lytic to latent?

A
  • lytic replication immediately follows viral entry (linear genome)
  • once contact with CD21 receptor expressing B cells is made with EBV gp350, the virus enters the B cells and becomes latent (circular genome)
  • the virus can then be reactivated back to lytic replication
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11
Q

How can EBV lytic infection be treated?

A
  • replication uses DNA polymerase
  • Acyclovir can be phosphorylated by viral kinases that are only expressed in the lytic cycle
  • it is converted into acyclovir triphosphate which can terminate viral DNA synthesis
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12
Q

What can be seen from EBV infected cells placed in culture?

A
  • EBV infected B cells give rise to a spontaneous out growth of EBV transformed cell line
  • this is called lympoblastoid cell lines (LCL)
  • LCLs can also be generated by infecting resting B cells with EBV which is useful for research
  • every cell in LCLs express a limited set of viral gene products
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13
Q

What latency type do EBV encoded genes belong in?

A
  • Type l = EBNA1, EBER1/2
  • Type ll = EBNA1, EBER1/2, LMP1/2
  • Type lll = EBNA1/2/3, EBER1/2, LMP1/2
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14
Q

Which latency types are found in different EBV infected cells?

A
  • in epithelial cells, only ll is found
  • in naive B cells, lll is found
  • in GC infected cells, ll is found
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15
Q

What is the function of EBV gene EBNA1?

A
  • expressed in all EBV infected cells irrespective of latency type
  • found in nucleus
  • role in maintenance of genome through binding to origin of replication and allowing replication
  • not recognised by cytotoxic T cells
  • contains Gly-Ala repeat sequences to prevent degradation
  • increases survival of infected B cells
  • binds to p53 regulatory protein USP7 to lower p53 levels
  • could be a target for future therapy
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16
Q

What is the function of EBV gene EBNA2?

A
  • found in nucleus
  • transcriptional regulator and activator of several viral and cellular genes (eg LMP1/2 and CD23)
  • interacts with DNA binding protein RBP-Jk to activate LMP and CD23
  • deletion results in inability to transform B cells
  • phosphorylation results in suppressed activity
17
Q

What is the function of EBV gene EBNA3?

A
  • comprised of 3 related proteins (EBNA3A/B/C)
  • found in nucleus
  • function as transcriptional regulators
  • 3A and 3C are essential for B cell transformation, 3B is dispensable
  • EBNA3 proteins associate with RBP-Jk transcription factor
18
Q

What is the function of EBV’s LMP1?

A
  • found in membrane
  • main transforming protein of EBV
  • major effector of virus induced cellular changes
  • inhibits apoptosis by activating NFkB
19
Q

What is the function of EBV’s LMP2?

A
  • found in intrinsic membrane
  • prevents EBV infected B cells from entry into lytic cycle
20
Q

What is the function of EBER1/2?

A
  • non-polyadenylated RNAs that are essential for EBV transformation of B cells
  • induce IL-10 to suppress cytotoxic T cells
21
Q

What is Burkitt’s lymphoma?

A

A disease caused by EBV

22
Q

What are the symptoms of BL?

A
  • abdominal inflammation
  • swollen lymph nodes
  • weakness/paralysis
  • sweating
  • weight loss
23
Q

What is endemic BL?

A
  • type of BL caught by children in Africa who have reduced resistance due to chronic malaria infections
  • effects 2-16 yrs old
  • tumour doubles every 24 hours so needs urgent treatment or will be fatal
  • can be treated with cyclophosphamide which induces apoptosis to shrink tumour
24
Q

What are the 3 types of BL?

A
  • Endemic = children in Africa/New guinea)
  • Sporadic = children/adults outside the endemic areas (15-20% EBV/30-40% HIV)
    Immunodeficiency related = in association with HIV
25
Q

What latency type is mostly exhibited in BL?

A

Type l latency

26
Q

How does EBV cause BL?

A
  • all BL cases carry 1 of 3 chromosomal translocations that place the MYC gene under regulation of the Ig heavy chain
  • this deregulates c-Myc expression
  • BL is associated with malaria/HIV which increases the chances of MYC translocation
  • EBV provide a pool of B infected cells to aid c-MYC translocation
  • EBNA1 aids cell survival and prevents apoptosis
27
Q

What is nasopharyngeal carcinoma (NPC)?

A
  • a rare tumour arising from the epithelium of the nasopharynx
  • more common in east Asia and Africa
  • EBV and dietary/genetic factors are associated with NPC
  • smoking/alcohol consumption and exposure to certain metals are also risk factors
  • 50-70% of tumours show detectable LMP1 protein and 100% have LMP1 transcripts
28
Q

What are the symptoms of NPC?

A
  • blood stained post nasal discharge
  • impaired hearing
  • tinnitus
29
Q

Which 3 ways do NPC tumours present?

A
  1. Proliferative growth causing nasal obstruction
  2. Ulcerative causing epistaxis
  3. Infiltrative causing cranial nerve involvement
30
Q

What treatments are there for NPC?

A
  • external beam radiation therapy
  • combination of chemo and radio therapy
  • recurrent/persistent NPC is still a challenge to treat
31
Q

What is the structure of LMP1?

A
  • 66kDa integral membrane protein comprising of short amino acid N-terminus, six hydrophobic alpha-helical transmembranes and a C-terminal tail
32
Q

What is the role of LMP1 and p53 in NPC?

A
  • majority of NPC tumouors contain p53 genes and LMP1 can modulate its activity
  • LMP1 has a growth advantage in tumours containing mutated p53 genes
  • LMP1 can also repress p53 mediated DNA repair
33
Q

How is protein synthesis in NPC inhibited by elF2a

A
  • PKR is activated through antiviral mechanisms
  • active PKR phosphorylates polypeptide chain initiation factor elF2a which inhibits protein synthesis
  • prolonged inhibition will lead to apoptosis
34
Q

How does EBER1 function in vivo?

A
  • expression inhibits PKR and protects against IFN induced apoptosis
  • it expresses growth factors IL-9 and IL-10

Biology of Cancer (19 decks)

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