Immunology 14 Viruses That Infect Lymphocytes: Ebv And Hiv

Front 1

Describe the Epstein-Barr virus

Back 1

-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

Front 2

Describe the human immunodeficiency virus (HIV-1)

Back 2

-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

Front 3

What are some mechanisms to avoid immune surveillance

Back 3

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

Front 4

How does EBV evade the immune system?

Back 4

EBV virus can persist by changing an anchor residue of the MHC. This makes it so that the viral peptide cannot be presented

Front 5

Describe how the age of host influences character of primary EBV infections

Back 5

-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")

Front 6

Describe EBV-driven neoplasms

Back 6

-Nasopharyngeal carcinoma, gastic cancer subset

-B cell lymphomas
-Burkitt's Lymphoma
-Immunoblastic lymphoma in immunosuppressed host
-Subset of Hodgkin's disease

Front 7

Describe the genetics of EBV

Back 7

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.

Front 8

What are the stages of EBV infection?

Back 8

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

Front 9

How does EBV work?

Back 9

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.

Front 10

Describe IgM antibodies for EBV

Back 10

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

Front 11

Describe IgG antibodies for EBV

Back 11

IgG anti VCA appears at time of clinical presentation and persists lifelong-"standard EBV titre"

Front 12

Describe the EA peak in EBV

Back 12

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

Front 13

How are EBV lytically infected cells eliminated?

Back 13

Largely by EBV-specific cytotoxic CD8 T cells (atypical lymphocytes), NK cells, interferon-mediated mechanisms and ADCC

Front 14

When does the latent phase of EBV infection take place? What cells are infected?

Back 14

3-6 weeks
B cells

Front 15

When do latent EB nuclear antigens (EBNA's) appear in EBV infection? How long do they last?

Back 15

They appear 3-6 weeks after initial infection
Last lifelong

Front 16

Describe the cytotoxic immune response when the EBV virus is in its latent form

Back 16

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.

Front 17

What occurs with failure of CD8 function in EBV infection?

Back 17

-Immunoblastic lymphoma
-Burkitt's lymphoma

Front 18

Describe EBV latency

Back 18

EBV is maintained in its latent infective cycle as a multicopy circular 172Kd ds plasmid minichromosome with replication linked to B cell proliferation

Front 19

What is EBNA1? What does it do?

Back 19

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.