10.3 EBV and KSHV – Flashcards
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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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