10.3 EBV and KSHV – Flashcards

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