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41 Cards in this Set
- Front
- Back
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Human T cell Leukemia Virus
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-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 |
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HTLV-1
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-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 |
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Tropical Spastic Paraparesis
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-chronic neurodegenerative syndrome
-causes progressive demyelinatin of motor neurons of spinal cord -seropositive for HTLV-1 -referred to as HAM (HTLV-1 Associated Myelopathies) |
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Tax
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-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 |
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Transfusion HTLV
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-breast feeding, sexual intercourse, blood, pregnancy
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HTLV through Breast milk
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-passage of infected lymphocytes (major)
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HTLV through Blood
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-whole blood transfer infected cells
-cell-free blood (plasma, IGs) do not spread it (unlike HIV) |
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HTLV through pregnancy
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-transplacental passage infected maternal lymphocytes
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HTLV through sexual contacts
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-male to female through HTLV infected cells
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HTLV genome
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-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 |
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Rex
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-phosphoprotein that regulates processing of viral mRNA
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Cellular transformation by HTLV-1
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-by viral tax protein
-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 |
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HTLV-1 to ATL
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-two phases HTLV:
1. IL-2 dependent growth phase 2. IL-2 independent growth phase |
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IL-2 dependent growth phase
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-polyclonal T cell proliferation
-IL-2 autocrine/paracrine loop |
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IL-2 independent growth phase
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-emergence monoclonal leukemic T-cells
-accumulation mutations |
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HTLV transformed T cells
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-multinuclear transformed
-presence IL-2/15/x, interferon gamma (IFN) and tumour necrosis factor alpha (TNF alpha) -chromatin highly condensed |
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CREB binding domain
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-cyclic-AMP repsonse element binding
-part of nuclear localisation domain of Tax protein |
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Activation of gene expression by Tax
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-involves:
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 |
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Tax and ATF/CREB
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-formation Tax complex with CREB/ATF at 21 bp
-recruits CBP/p300 |
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Tax and CBP/p300
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-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 |
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CBP
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-part of RNA pol II holoenzyme complex
-has instrinsic histone acetylation activity, can recruit transcription machinery |
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Tax and NF-KB
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-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 |
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Tax and cell growth/proliferation
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-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 |
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Tax and ATF/CREB and CBP
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-viral genome/LTR transcription
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Tax and NF-kB and p300
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-immune and inflammatory pathways
-cellular proliferation |
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Tax and SRF
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-cellular proliferation
-cellular differentiation |
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ATL
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-pre-ATL
-smoldering -chronic -lymphoma -acute (worst) -aggresive and fatal leukemia of CD4+ T cells -long latency period |
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Pathogenesis HAM/TSP
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-3 methods:
1. autoimmune model 2. direct infection model 3. bystander damage model -long latency period -factors possibly contributing to ATL of HAM |
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Autoimmune Model HAM/TSP Pathogenesis
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-HTLV-1 activates autoreactive T cells
-T cells migrate to CNS and recognise Ag on CNS cell and destory them |
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Direct Model HAM/TSP Pathogenesis
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-persistent HTLV-1 infection and activation in CNS leads to tissue destruction
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Bystander Damage Model HAM/TSP Pathogenesis
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-infected T cells from blood to CNS cause inflammation reaction
-reaction destory healthy CNS tissues |
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Detection HLTV
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-proteins by Western blot (SDS-PAGE gel, nitrocellulose, antibodies)
-DNA sequences (PCR) -antibodies against HTLV (ELISA) |
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Treatment HTLV
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-chemotherapeutic not successful in ATL (leukemia)
-use AZT and IFNalpha -rapamycin -cholorsporin A -vaccines -oncolytic viruses |
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AZT
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-anti-retroviral drug causing chain termination
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INFalpha
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-anti-proliferative effects on cells
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Rapamycin
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-immunnosuppressive drug
-anti-proliferative effects on T cells derived from HAM patients -only in vitro |
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Cyclosporin A
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-immunosuppresor
-reduced spontaneous proliferation T cells in HAM patients |
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Vaccination
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-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 |
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Classical vaccines
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-purified viral proteins
-attenuated virus |
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Novel vaccines
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-DNA vaccines
-new kind |
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Oncolytic viruses
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-new therapeutic approach?
-PBMC taken from patient -VSV virus could not replicate in pressence PBMC -PBMC maintains apoptosis levels (monitored by protein annexin 5) |
