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19 Cards in this Set

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Describe the Epstein-Barr virus
-Large DNA virus, e.g. herpesvirus
-Coevolved with host species over millions of years
-Genetically stable
-Persists in host in latent pattern of viral gene expression in response to T cell surveillance
Describe the human immunodeficiency virus (HIV-1)
-RNA retrovirus
-Recently introduced into humans
-Error-prone viral replication mechanisms resulting in "swarms" of distinct strains "quasispecies"
-Overwhelms host by escaping from immune surveillance
What are some mechanisms to avoid immune surveillance
1. Avoid recognition by cytotoxic T cells
-Viral strains evolve that avoid presentation by p-MHC: mutate amino acids
-Anchor peptide to MHC
-Recognition by T cells (immunodominant)
-Block steps of antigen processing

2. Modification of the immune response
-Release of anti-inflammatory cytokines, IL-10

3. Suppression of viral expression by virus latency
-Change from productive to latent mode by selective pressure of immune response
How does EBV evade the immune system?
EBV virus can persist by changing an anchor residue of the MHC. This makes it so that the viral peptide cannot be presented
Describe how the age of host influences character of primary EBV infections
-Primary infection with EBV in childhood usually subclinical

-25-70% of newly infected adolescents and adults develop infectious mononucleosis
-Fever
-Lymphadenopathy
-Pharyngitis
-Transient heterophil antibodies
-Activated CD8 cytotoxic anti EBV T cells ("atypical lymphocytosis")
Describe EBV-driven neoplasms
-Nasopharyngeal carcinoma, gastic cancer subset

-B cell lymphomas
-Burkitt's Lymphoma
-Immunoblastic lymphoma in immunosuppressed host
-Subset of Hodgkin's disease
Describe the genetics of EBV
EBV incorporates itself as a replicating element. Very rarely does it enter the human genome. It stays as a little plasmid, with its own origin of replication. It replicates in parallel with the chromosomes. In this setting it can give rise to two classes of neoplasms. One is related to epithelial cell invasion by the virus. The prototypical one is nasopharyngeal carcinomas. These occur primarily in SE asia, southern China, Papua New Guinea. A subset of gastic cancers. More globally are B cell lymphoma effects. The Burkitt's lymphoma is more characteristic of the malaria belt in Africa. There is a subset of Burkett-like lymphomas in the US. During immunosuppression, one suppresses the CD8 response that maintains EBV in its latent form. This occurs during the immunosuppression during autoimmune disease or transplantation. This runs the risk of allowing the virus to go back into a more productive and transforming form. Immunosuppresed patients can develop immunoblastic lymphoma. Often this can be reversed through removal of the immunosuppression.
What are the stages of EBV infection?
EBV is a B cell lymphotropic herpesvirus

Binding EBV surface glycoprotein to CD21 (CR2)
-CD21 expressed on B cells as BCR co-receptor complex with CD19
-CD21 also expressed on some epithelial cells, accounting for tropism

Triggers T-independent polyclonal B cell activation Ig synthesis and B cell proliferation

Results in T-independent release of heterophil and other antibodies (rheumatoid factor, cold agglutinins, ANA)

EBV enters the cell by receptor mediated endocytosis
How does EBV work?
The CD21-CD19 complex is a modulatory complex. When the virus binds the B cell it cross links sufficient antigens to fool that B cell into thinking that it has to drive to become a plasma cytoid cell and release antibody. It initiates the differentiation of the B cell independent of T cells. It is polyclonal because it binds to structures not cognitively part of the B cell clonal structure. The expression of low affinity antibodies, rhematoid factors, cold agglutinins and such is a transient event.
Describe IgM antibodies for EBV
IgM antibodies to Viral Capsid Antigens (VCA) and Early Antigens (EA) are found at clinical presentation indicating lytic replication and persists for 1-2 months
Describe IgG antibodies for EBV
IgG anti VCA appears at time of clinical presentation and persists lifelong-"standard EBV titre"
Describe the EA peak in EBV
Antibodies to EA peak at 3-4 weeks. The higher the EA peak, the longer the disease persists and the poorer you are handling the virus
How are EBV lytically infected cells eliminated?
Largely by EBV-specific cytotoxic CD8 T cells (atypical lymphocytes), NK cells, interferon-mediated mechanisms and ADCC
When does the latent phase of EBV infection take place? What cells are infected?
3-6 weeks
B cells
When do latent EB nuclear antigens (EBNA's) appear in EBV infection? How long do they last?
They appear 3-6 weeks after initial infection
Last lifelong
Describe the cytotoxic immune response when the EBV virus is in its latent form
The virus evades cytotoxic response in latent form. The CD8 T cells (atypical lymphocytes) play a crucial role in maintaining latency and kill productively infected B cells.
What occurs with failure of CD8 function in EBV infection?
-Immunoblastic lymphoma
-Burkitt's lymphoma
Describe EBV latency
EBV is maintained in its latent infective cycle as a multicopy circular 172Kd ds plasmid minichromosome with replication linked to B cell proliferation
What is EBNA1? What does it do?
One of 9 latent proteins. EBNA1 binds to the EBV ori, initiating replication and also acting as a transcriptional enhancer. EBNA1 contains a gly-ala repeat region that inhibits the ATP motor of the proteasome, impeding further insertion of EBNA1 into the proteasome, thus halting its degradation, a strategy for avoiding surveillance.