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10.3 EBV and KSHV
at 10:00 by Dr. Aiyer
74
Microbiology
Professional
10/03/2011

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Term
T/F EBV and KSHV diseases are mostly associated with latency.
Definition
true: small subset of viral genes expressed
Term
What is the genome of EBV and KSHV?
Definition
large linear dsDNA
Term
What's the size of the EBV genome?
Definition
165-180
Term
What's the size of the KSHV genome?
Definition
125-140 kb
Term
What is EBV tropism?
Definition
B lymhpocytes and epithelial cells
Term
hat percent of humans are EBV+?
Definition
95%
Term
What is the tropism of KSHV?
Definition
endothelial and epithelial cells (very small % in non-HIV+)
Term
How many proteins does the EBV genome encode?
Definition
94
Term
How many proteins does the KSHV genome encode?
Definition
86
Term
What is the structure of EBV and KSHV genome inside the host nucleus?
Definition
circular
Term
For EBV, only __ of the 94 portiens are necessary for cell proliferation (similar pattern in KSHV).
Definition
6
Term
What are the entry receptors for EBV?
Definition
MHC class II and CD21 on B cells
Term
What are the entry receptors for KSHV?
Definition
DC-SIGN and integrin alpha V beta 3
Term
What oral lesion is caused by EBV in AIDS patients?
Definition
oral hairy leukoplakia (epithelial hyperplasia)
Term
What are two colloquial names for infectious mononucleosis?
Definition
kissing disease or glandular fever
Term
What's the difference between acute and chronic mononucleosis?
Definition
acute resolves in <3-4 months without intervention
chronic is rare and persists for more than 6 months
Term
How do you diagnose mononucleosis by looking at lymphocyte differential?
Definition
normally B cells are about 10-15% of lymphocytes but in Mononucleosis 50% are B cells
Term
What causes the heterophile IgM response?
Definition
EBV-induced differentiation of B-cells into proliferating blasts that secrete their preprogramed antibody
Term
What is the bunnel test?
Definition
heterophile IgM agglutinate sheep RBCs
Term
How do you diagnose mono?
Definition
bunnel test, IgM response against virus capsid antigen, IgG response against EBV nuclear proteins= both antibody responses are seen after diseaes resolution
Term
What is the tx for acute mono?
Definition
acetominophen (tx symptoms)
Term
What is the tx for chronic mono?
Definition
corticosteroids, esp prednisone (suppreses production of IL-1alpha by neutrophils which stimulates B-cell proliferation)--> reduces lymph node and tonsilar swelling
Term
Are anti-herpetics effective in treating mono?
Definition
clinical trial results: reduced cell-free viral load, no reduction in disease course or alleviation of symptoms (dz is caused by proliferation of latently infected b cells not viremia); possibly useful in severe chronic disease
Term
How do B cells proliferate?
Definition
CD40 on B to CD40L on CD4; MHCII to CD4. Starts NFKB and AP-1 signaling cascades in B cell. B cell activation and proliferation
Term
How do B cells become plasmablasts in EBV infection?
Definition
notch on B cell binds to deltex on T cell, neutrophil or NK cell
Notch-dependent "suppressor of hairless" pathway that promotes differentiation to antibody-secreting blast. plasmablast normally undergo apoptosis when antigen disappears.
Term
What is the function/mechanism of LMP1?
Definition
activates NFKB and AP-1 pathways without a ligand (normally CD40 and CD40 L)
Term
What is the function/mechanism of EBNA2?
Definition
activates suppressor of hairless pathway without a ligand (notch + deltex)
Term
What is the function of EBNA 3 and EBNA1?
Definition
block apoptosis, so EBV+ cells don't die (have other functions as well) **most plasmablasts undergo apoptosis**
Term
How does EBV's EBNA-1 help evade the immune response by regulating replication?
Definition
restricts viral replication to once per cell cycle to prevent being recognized by immune cells
Term
How does EBNA-1 prevent viral antigens from being efficiently presented?
Definition
EBNA1 has long (~250aa) repeat of glycine and alanine that associates with the proteosome but can't be easily degraded. Therefore, other viral antigens aren't efficiently presented
Term
How do you go from EBV B cell proliferation to cancer?
Definition
cell cycle checkpoints lost = immortalized cell with the capacity to proliferate but still responds to cues that limit proliferation
differentiation/apoptosis/response to DNA damage= transformed cells that proliferate in an uncontrolled manner leads to metastasis, etc.
Term
EBV was first isolated from...
Definition
Burkitt's lymphomas from children in sub-saharan africa
Term
What was the first human tumor virus to be identified?
Definition
EBV
Term
How often do EBV and burkitt's lymphoma correspond?
Definition
100% of endemic burkitt's and >50% of sporadic burkit's lymphoma
Term
What is the classical histological finding of EBV/burkit's lymphoma?
Definition
small, noncleaved B cells in lymph nodes
Term
What are the symptoms of Burkit's lymphoma?
Definition
unexplained swollen lymph nodes that expand rapidly in size but are painless. Endemic BL often has a jaw bone or thyroid presentation. Sometimes endemic and almost always sporadic BL can have a unexplained rapidly expanding generally painless abdominal mass
Term
What are the molecular characteristics of BL?
Definition
EBNA1 but no other EBV proteins present
chronosomal translocation that activates the c-myc protooncogene t(8:14)
Term
How many new lymphomas are there each year in the US?
Definition
approx 74,000 new lymphomas per year
Term
How many lymphoma-associated mortalities are there per year?
Definition
21,500
Term
What percent of lymphomas are EBV positive?
Definition
80-85%
Term
What is the five-year survival rate of lymphomas?
Definition
60-80% (state and metastasis dependent)
Term
T/F Lymphoma has a higher annual diagnosis and annual mortality than leukemia, cervical cancer, and melanoma.
Definition
true
Term
Is the 5 year survival rate better for lymphoma or leukemia?
Definition
lymphoma (60-80%) better than leukemia (50%)
Term
Kaposi's sarcoma and _____ were the earliest AIDS defining malignancy in 1985.
Definition
EBV-positive lymphomas
Term
T/F The increase in annual US lymphomas is largely due to EBV-positive lymphomas in AIDS.
Definition
true
Term
What are the AIDS associated lymhpomas?
Definition
CNS lymphomas, immunoblastic lymphomas, burkitt's lymphoma, primary effusion lymphoma, hodgkin's disease
Term
CNS lymphoma is an AIDS associated lymphoma if...
Definition
EBV+; LMP1, EBNA1,2,&3
Term
Immunoblastic lymphoma is AIDS-associated if..
Definition
EBV+; LMP1, EBNA1,2,3
Term
What percent of AIDS associated burkit's lymphoma is EBV positive?
Definition
80% (only EBNA1, chromosomal translocation)
Term
Primary effusion lymphoma is AIDS associated if...
Definition
EBV/KSHV double positive; at least EBNA-1
Term
What percent of AIDS associated Hodgkin's disease is EBV positive?
Definition
50%
Term
What is the effect of HAART on lymphomas?
Definition
decreases the percent of EBV and KSHV positive lymphomas. PreHAART EBV positivity was 88%, KSHV was 6.5%. HAART era EBV positivity is 60% and KSHV positivity is 2.5%
Term
T/F HAART has caused the incidence of lymphoma to rise.
Definition
true, lymphoma incidence increases due to HAART dependent increased life-span
Term
How does EBV enhance CNS and immunoblastic lymphoma proliferation?
Definition
provides proliferative signals (LMP1 and EBNA2)
provides anti-apoptotic signal (EBNA1 and EBNA3)
Term
How does EBV enhance Burkitt's lymphomas?
Definition
provides anti-apoptotic signals via EBNA1
Term
What are three main KSHV genes that are similar to EBV genes?
Definition
K1, vFLIP, LANA
Term
What is the function of K1?
Definition
activates NFKB, NFAT pathways to cause B-cell proliferation (like EBV's LMP1)
Term
What is the function of vFLIP?
Definition
blocks apoptosis (like EBNA1 and 3 of EBV)
Term
What is the function of LANA?
Definition
genome replication (like EBNA1 of EBV)
Term
What patient populations are susceptible to kaposi's sarcoma?
Definition
indolent disease in elderly mediterranean men
aggressive disease in HIV+ men
Term
What is the appearance of kaposi's sarcoma?
Definition
bluish-black papular nodules seen on the skin but also elsewhere including the gastrointestinal and respiratory tract
Term
What cells are proliferating in Kaposi's sarcoma?
Definition
highly vascularized spindle cells
Term
What is the therapy for Kaposi's sarcoma in HIV+?
Definition
HAART, radiation, cyrosurgery, interferon alpha
Term
What is primary effusion lymphoma?
Definition
lymphoma of pericardium or pleural cavity. also called body cavity lymphoma. Very poor prognosis and highly resistant to therapy
Term
What % of primary effusion lymphomas are KSHV positive? KSHV/EBV double positive?
Definition
100% (?)
>80%
Term
What is lymphoma chemotherapy?
Definition
Cyclophosphamide, hydroxydaunorubicin, oncovin, (methotrexate), prednisone
Term
What is the function of cyclophosphamide?
Definition
damages DNA by akylation to block DNA replication
Term
What is the function of hydroxydaunorubicin?
Definition
intercalates into DNA, reduces gene expression, causes DNA damage
Term
What is the function of oncofin?
Definition
interferes with tubulin to block mitosis
Term
What is the function of methotrexate?
Definition
inhibits DHFR to reduce nucleotide biosynthesis
Term
What is the function of prednisone?
Definition
decrases IL-1alpha to reduce B cell proliferation
Term
Do EBV+ lymphomas respond to CHOP/CHOMP therapy?
Definition
although they are high-grade lymphomas they respond well except for PEL
Term
Which are more recalcitrant to therapy, reccurrent EBV+ lymphomas or EBV- lymphomas? why?
Definition
EBV+
some EBV proteins (LMP1, EBNA1) promote mutagenesis
Term
What therapy is used for CHOMP resistant lymphomas?
Definition
rituximab (rituxan)= monoclonal antibody against CD20. More recently, autologous CTL therapy against EBV positive lymphoma cells is effective against some lymphomas
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