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41 Cards in this Set

  • Front
  • Back
Human T cell Leukemia Virus
-discovered by Robert Gallo, 1980 as first human retrovirus
-member human retrovirus family
-5 members: HTVL-I, HTLV-II, HIV-1, HIV-2, Human foamy virus
-etiological agent of ATLL and TSP/HAM
-not ubiquitous, Asia
-2-4% will develop HAM/TSP
-diagnosed with cutaneous T cell Leukemia
-later renamed ATLL (adult T cell leukemia/lymphoma)
-can infect many cells but only CD4+ cells (mechanism unknown) in vivo due to a transactivator, Tax
-1% will develop clinical diseases (ATL or HAM...), 1/4 will develope HAM
-infection later in life, more in females
-can cause leukemogenesis therefore ATL
Tropical Spastic Paraparesis
-chronic neurodegenerative syndrome
-causes progressive demyelinatin of motor neurons of spinal cord
-seropositive for HTLV-1
-referred to as HAM (HTLV-1 Associated Myelopathies)
-transactivator (activator domain)
-possible for HTLV-I to infect CD4+ T cells
-essential for transformation T cells
-sequence found 21 bp in viral transcription
-plays role in leukemogenesis
-activates cellular transcription factors which activate viral and cellualr gene transcription
-induces T-cell activation and proliferatoin through IL-2 autocrine loop
-induces G1 to S transition leading to immortalisation
-40kDA protein, nuclear localisation signal (also a CREB binding domain)
-integrates into host genome (oncoprotein) and interacts with 3' LTR then production mRNA
Transfusion HTLV
-breast feeding, sexual intercourse, blood, pregnancy
HTLV through Breast milk
-passage of infected lymphocytes (major)
HTLV through Blood
-whole blood transfer infected cells
-cell-free blood (plasma, IGs) do not spread it (unlike HIV)
HTLV through pregnancy
-transplacental passage infected maternal lymphocytes
HTLV through sexual contacts
-male to female through HTLV infected cells
HTLV genome
-same as other retroviruses (gag, pol, env, LTR)
-LTR very active sites, required for insertion, activation, transcriptional regulation
-single and double spliced to yield proteins
-phosphoprotein that regulates processing of viral mRNA
Cellular transformation by HTLV-1
-by viral tax protein
-plays role in leukemogenesis
-activates cellular transcription factors which activate viral and cellualr gene transcription
-induces G1 to S transition leading to immortalisation
-two phases HTLV:
1. IL-2 dependent growth phase
2. IL-2 independent growth phase
IL-2 dependent growth phase
-polyclonal T cell proliferation
-IL-2 autocrine/paracrine loop
IL-2 independent growth phase
-emergence monoclonal leukemic T-cells
-accumulation mutations
HTLV transformed T cells
-multinuclear transformed
-presence IL-2/15/x, interferon gamma (IFN) and tumour necrosis factor alpha (TNF alpha)
-chromatin highly condensed
CREB binding domain
-cyclic-AMP repsonse element binding
-part of nuclear localisation domain of Tax protein
Activation of gene expression by Tax
1. activating transcription factor/CREB (ATR/CREB)
2. CREB binding protein (CBP) and p300
3. nuclear factor - kB (NF-kB)
4. serum response factor (SRF)
-Tax affects all above transcription factors by:
a) increasing transcriptioin factor dimerisation to active forms
b) increasing nuclear translocation of TXN factors
Tax and ATF/CREB
-formation Tax complex with CREB/ATF at 21 bp
-recruits CBP/p300
Tax and CBP/p300
-CBP/p300 complex strong transcriptional activating enhancer of HTLV LTR
-tax binds CBP uses coactivator properties to stimulate transcription viral genome (only few genes transcribed)
-Tax binds and sequesters CBP through CBP KIX domain, competes with cellular TFs like c-Myc, c-Jun, p53 for CBP (produced so virus can override cellular TFs)
-altered gene expression in HTLV-1 infected cells, favours genes involved in HTLV-1 replication adn pathogenesis
-part of RNA pol II holoenzyme complex
-has instrinsic histone acetylation activity, can recruit transcription machinery
Tax and NF-KB
-two ways can interact with immune cell activation
-interacts with NF-kB family members: p65 (RelA), cRel, RelB, p50, p52
-tax enters nucleus and promotes NF-kB dimerisation of active complexes (p50/p50 and p65/p50) and binding to kB sites in promoter of genes
-leads to activation of transcription
Tax and cell growth/proliferation
-inhibits p53, preventing repair and apoptosis
-interacts with cytokines, receptors, surface proteins, oncogene products and growth factors as viral attempts to drop host cell defenses and upregulate growth
-binds cellular transcription factors and targets them to specific promoters
-acts as a molecular bridge to bring transcription factors bound to DNA in close proximity to transcriptional coactivators
-interactions result in preferential activatin genes regulated by Tax-interacting partners
Tax and ATF/CREB and CBP
-viral genome/LTR transcription
Tax and NF-kB and p300
-immune and inflammatory pathways
-cellular proliferation
Tax and SRF
-cellular proliferation
-cellular differentiation
-acute (worst)
-aggresive and fatal leukemia of CD4+ T cells
-long latency period
Pathogenesis HAM/TSP
-3 methods:
1. autoimmune model
2. direct infection model
3. bystander damage model
-long latency period
-factors possibly contributing to ATL of HAM
Autoimmune Model HAM/TSP Pathogenesis
-HTLV-1 activates autoreactive T cells
-T cells migrate to CNS and recognise Ag on CNS cell and destory them
Direct Model HAM/TSP Pathogenesis
-persistent HTLV-1 infection and activation in CNS leads to tissue destruction
Bystander Damage Model HAM/TSP Pathogenesis
-infected T cells from blood to CNS cause inflammation reaction
-reaction destory healthy CNS tissues
Detection HLTV
-proteins by Western blot (SDS-PAGE gel, nitrocellulose, antibodies)
-DNA sequences (PCR)
-antibodies against HTLV (ELISA)
Treatment HTLV
-chemotherapeutic not successful in ATL (leukemia)
-use AZT and IFNalpha
-cholorsporin A
-oncolytic viruses
-anti-retroviral drug causing chain termination
-anti-proliferative effects on cells
-immunnosuppressive drug
-anti-proliferative effects on T cells derived from HAM patients
-only in vitro
Cyclosporin A
-reduced spontaneous proliferation T cells in HAM patients
-best form immunity
-virus must display relatively low antigenic variability (not HIV)
-natural immunity in humans must occur
-experimental vaccines with envelope antigens must be successful
Classical vaccines
-purified viral proteins
-attenuated virus
Novel vaccines
-DNA vaccines
-new kind
Oncolytic viruses
-new therapeutic approach?
-PBMC taken from patient
-VSV virus could not replicate in pressence PBMC
-PBMC maintains apoptosis levels (monitored by protein annexin 5)