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34 Cards in this Set

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EBV Virus
1) DNA or RNA virus
2) Has it been around awhile?
3) Is it stable?
4) In what form does it persist?
1) Large DNA virus
2) It has coevolved for millions of years
3) It is genetically stable
4) It persists in latent phase, in response to CD8 T cell surveillance.
What are three strategies viruses employ to evade the host immune response?
1) Avoid MHC presentation by mutating MHC class 1 molecule or simply blocking the antigen processing and presentation (ex. tap protein)
2) Enter latent phase, suppression of viral gene expression
3) Modify the immune response via release of anti-inflammatory cytokines, IL-10 TGF-beta, etc.
How does age affect the presentation of EBV primary infection?
Young children infected usually don't present with symptoms, while adolescents and adults present with typical Mono symptoms: including elevated CD8 cytotoxic anti EBV T cells and transient heterophil Ab
What are common neoplasms caused by EBV virus?
Nasopharyngeal carcinoma
B-cell lymphomas:
Burkitt's
Immunoblastic lymphoma in
immunosuppressed
Subset of Hodgkin's disease
Describe the following stages of EVB infection:
a) Binding (via what molecule and to which cell types)
b) What does binding cause?
c) How does EBV enter the cell
a) EBV binds the CD21 (CR2) receptor expressed as a coreceptor with CD19 on B cells and expressed alone on some epithelial cells (which causes tropism)
b) Binding induces T-cell independent B cell activation, Ig sythesis, and proliferation leading to the T-cell independent release of heterophil (Ab which are cross reactant) and other Ab (Rheumatoid factor, cold agglutinins, etc.)
c) via receptor mediated endocytosis
The initial EBV lytic infection stage: For the following Ab, list where they are found when, to what Ag, and for how long they persist
1) IgM antibodies
2) IgG antibodies
1) IgM Ab are found to Viral Caspid Antigens (VCA) and Early Antigens (EAs) at clinical presentation, representing lytic replication. They persist 1-2 months
2) IgG to VCA appears at time of clinical presentation is lifelong (standard EBV titer)
IgG to EA peak at 3-4 wks and are marker of more severe disease
Latent phase of EBV infection
1) What happens in this time?
2) What is the time frame?
3) What Ab are found?
1) HBV in B cells remaining after lytic phase enter latent phase to evade cytotoxic response
2) 3-6 wks
3) Ab to latent EB Nuclear Antigents (EBNA) appear at 3-6 wks and are lifelong
During the Initial EBV lytic infection stage how are infected cells killed?
EBV specific cytotoxic cells, NK cells, interferon-mediated mechanisms and ADCC
What is the role of the adaptive immune system in the latent phase of the EBV virus?
The CD8 T cells keep the virus in the latent and thwart any attempt of EBV to proliferate in the B-cells by killing any B-cell with active EBV replication.
How does EBV survive in its latent from within the B cell and how does it avoid surveillance?
The EBV laten virus is maintained as a multicopy circular plasmid with replication linked to B-cell proliferation. It expresses 9 latent proteins (six nuclear Ag, EBNA 1, 2, 3A, 3B, 3C, and EBNA-LP, and six membrane, LMP1, LMP2A, LMP2B) EBNA 1 is crucial to the viruses ability to replicate and avoid surveilance.
EBNA1: Describe its role in EBV replication and avoidance of immune surveilance
EBNA1 bind the ori on EBV initiating replication and acting as a transcriptional enhancer. It also has gly-ala residues that inhibit the ATP motor of the proteosome, impeding EBNA1 degradation and presentation on MHC Class 1.
BCLC: B-cell lymphoblastoid cell line
What EBV and B-cell genes are expressed in BCLC cells and what do they indicate?
BCLC express all of the latent phase proteins of EBV (termed latency III) as well as many B-cell activation markers and cellular adhesion molecules. This implies that the EBV virus and B-cells are rapidly proliferating and clumping together when grown in tissue culture.
Immunoblastic lymphoma
1) In what individuals does this disease develop?
2) What EBV genes are expressed?
3) Are proliferations monoclonal or polyclonal?
4) Is it treatable?
5) What is the phenotype?
6) What does this type of lymphoma tell us about our T-cells and BLCL
1) Patients recieving T cell immunosuppressive therapies
2) All the EBV latent genes.
3) The being as polyclonal but can undergo a transformation to monoclonal
4) The polyclonal form usually resolves with the withdrawal of immunosuppressants. The monoclonal is more difficult to treat.
5) Similar to BCLC phenotype
6) We are all on the verge of BCLC but our CD8 T-cells keep it in check.
Burkitt's Lymphoma
1) Where is this found and what is the state of the immune systems in the patients with this disease?
2) What is the EBV expression?
3) What is the lymphoma expression?
4) What is the phenotype, how do the B cell lines grow?
1) This is found in Africa where individuals immune systems are overworked
2) Only EBNA1 is abundantly transcribed (latency 1)
3) Distinct phenotype of CD10 and CD77 but no activation or adhesion molecules
4) These B cell tumor lines grow as dispersed single cells
What is the signficance of the HLA-A11 gene distribution in relation to the development of nasopharyngeal carcinomas from EBV infection?
HLA-A11 respond to two specific epitopes of the EBV EBNA3A (EBNA4) virus. In China and Papua New Guniea, where more than 50% of individuals carry this allele, the virus mutated and the MHC no longer can recognize the EBNA4. This allows the EBV virus to escape surveillance and is commonly seen in neoplastic transformation.
Organization of HIV-1Provirus
1) LTR: Long term repeats
2) Envelope protein
3) Polymerase
1) At each end of the provirus, and are important for insertion into the DNA as well as initiation of transcription
2) The infectious parts, mediated binding to CD4 and chemokines receptors as well as fusion to the membrane
3) Polymerase is necessary for reverse transcription
Stages of HIV Infection
1) Fusion (via envelope protein interaction with membrane receptor comples (CD4 and chemokineR /conformational change)
2) Uncoating
3) Reverse transcription on microfilaments--> Pre- integration complex
4) Nuclear import
5) Integration
Host Response to HIV infection
1) First phase: effector cells and sxs
1) CD8 T-cell response controls initial destruction of memmory effector CD4 cells but does not completely eliminate virus in CD4s and monocytes. Antibodies to HIV but these don't clear or protect from the infection. This phase is represented by flu sxs in the acute illness and then a latent phase that can last 12 years
Host Response to HIV infection
2) Second phase
HIV virus escaped CD8 response and mutations in the viral envelope lead to infection and destruction of CD4 T-cells. AIDS appears with the loss of critical CD4 subsets.
What does the term "set point" refer to in HIV and what are its implications for the future course of the disease?
"Set point" refers to the lowest CD4 T-cell count during the acute illness phase, or flu like phase, prior to the latent phase. The extent of this T-cell drop is a good indicator for the future, the lower the drop the poorer the future (ie short latent phase=2yrs). A long term responder should have a slight drop followed by a long latent phase.
How accurate is HIV reverse transcriptase?
Not very, reverse transcriptase activity leads to a variety of mutations. This is a strategy to evade the CD8 T cell response.
CCR5
1) Bind what HIV protein?
2) What normal chemokines does it bind?
3) Where is it found?
4) What is its role in the immune response?
5) Polymorphisms and implications?
1) Bound by R5 tropic envelope protein as part of receptor complex
2) Bound by RANTES, MIP-1alpha and beta, inflammatory cytokines made by activated CD8/4 cells in response to HIV. These cytokines competitively bind with envelope protein for CCR5 and can block the progress of infection.
3) Monocytes, DC and effector, memmory and activated T-cells, NOT naive T cells
4) Recruit above molecules to site of inflammation
5) delta 32 has no CCR5 expression, and individuals homozygous for this cannot be infected with sexually transmitted HIV
CXCR4
1) Which two molecules compete for this receptor?
2) Where is is found?
3) Actions of CXCR4?
1) Bound by X4 tropic envelope protein as well as Stromal Derived Growth Factor (SDF-1), but this is not expressed in inflammation or by T-cells
2) Expressed in monocytes, naive T-cells, B-cells, etc. --> X4 preferentially invades naive T-cells
3) SDF-1/CXCR4 binding causes naive T-cells to move to lymph node
R5 Phase of HIV infection
Comment on mode of transmission, diversity, and cells affected.
Early infections are usually predominantly R5. R5 is almost always sexually transmissible and can replicate in monocytes. Mostly monocytes and macrophages are infected, with activated and memmory T-cells being infected as well but to a much lesser degree, and their population remains stable. However, T-cells infected with R5 virus can serve as reservoir for long lived latent virus. The R5 strain has limited diversity.
Significance and mechanism for R5 to X4 mutation
This change only requires a few changes in the V3 loop sequence of the envelope protein and leads to infection of naive T-cells and the loss of the ability to control viral replication --> AIDS
CD8 T-cell response to HIV-1
1) This response is present in which phase of the HIV infection?
2) How do CD8 cells accomplish this? What strategies do they use?
3) Is the response dependent on many different T cell clones?
1) The CD8 response begins during the acute flu like phase and continues during the latent asymptomatic phase (mostly R5 Phase)
2) a) Cytotoxic killing of virus infected macrophages and CD4 T-cells via perforin pathway and Fas
b) Strong inhibition of viral infectivity by release of chemokines that compete with R5 for CCR5 receptor complex necessary for R5 entry.
c) Release of IFN gamma and TNF alpha decreases LTR (long terminal repeat) driven transcription
3) Just a few CD8 T-cells with different immunodominant HIV peptides are responsible and comprise during infection 1-5% CD8 Tcell repetoire. The more clones you have recognizing different epitopes, the better the outlook.
Diffuse Infiltrative Lymphocytosis Syndrom (DILS)
Resembles Sjogren's Syndrome, classic signs of which are xerostomia and dry eyes. It results from an excessive anti HIV CD8 T cell response leading to infiltration of glands. This complication is actually associated with long term non progression and a favorable outlook but also associated with a type of B cell lymphoma.
Characteristics of Long Term Non Progressors (asymptomatic >12 yrs)
a) HLA-B27, B57 are particular HLA types associated with this b/c recognize several different epitopes
b) Low plasma virion levels <500
c) High CD8 T-cell counts >3000
d) High chemokine release (Rantes, and MIP)
e) CTL response is directed at critical HIV targets that cannot be eliminated without compromising the survival of the virus (Ex: env, pol, gag). This is KEY!
Describe viral escape in the context of HIV
Viral escape is when the virus is no longer presented by MHC class I and env begins to mutate at a more rapid rate, R5-->X4 and loss of "epitope war"
Causes of CD4 T-cell loss in HIV
1) Bystander effect
2) Thymic derangement
3) CTL
4) ADCc
5) CD4 T cell activation is linked to HIV replication
1) Many many CD4 T-cells are activated to respond during the antiviral response by cytokines. This simply leads to a loss of the CD4 T cell repetoire via physiologic apoptosis
2) Thymic loss prevents formation of new CD4 T cells
3) CD8 cells kill infected CD4s
4) ADCC by NK cells of infected CD4s
5)cyclin t1, NFAT, and NFkB released during Tcell activation leads to HIV replication (via cyclin 9/RNAP2)
What is AIDS?
Consequence of progressive CD4 loss
Stages of AIDS in relation to loss of immune function
1) Loss of Ag-specific clonal responses, ie memmory responses
2) Loss of ability to generate new CD8
3) Loss of Mixed Lymphocyt Culture responsiveness
4) Loss of PHA (?)
List AIDS associated infections in order relating to an increase in severity of immune deficiency
Candida
Salmonella
Mycobacterium TB reactivation
Activation of latent Herpes Zoster (shingles)
EBV --> polyclonal lymphomas
Pneumocystitis carini
Cytamegalovirus infections
Why have HIV vaccines failed?
Ab produced don confer protection and neither does vaccination which produces CD8 T cell immunity and in fact that infection may progress more rapidle.