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31 Cards in this Set
- Front
- Back
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What is HTLV? What are some of its features?
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Member of the RV family
Etiological agent of Adult T-Cell leukemia (A-TLV) Infects multiple types of T cells, but only CD4+ and CD25+ T cells will be transformed -Etiological agent og Tropical Spastic Paraparosis (HAM): demyelinating neuropathy disease -Encodes a unique transactivator, Tax |
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How does the viral load of HTLV differ form the viral load of HIV?
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HTLV: Viral load increases # of T cells
HIV: Viral load increases, causing a decrease in the amount of T-cells |
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What is Tax? What does it do?
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-Essential for transformation
-controls the early transcription of LTR of the virus -Strong transactivator that interfaces with othe paths wich is the likely cause of transformation |
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`What are the 2 diseases caused by HTLV?
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ATLL
HAM (neural pathology) |
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Where is HTLV prevalent?
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Japan
South America (neural pathology mostly) Central America (both pathologies) |
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How is HTLV transmitted?
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-Blood borne (but only in cellular blood prod. Cell-free blood products like plasma and Igs don't spread this virus)
-Pregnancy -Breast Milk -Sexual Contact (mostly male to female transmission. Female to male transmission is rare) **Not much virus is produced. Its the transfer of virus-infected cells that leads to transmission from patient-patient **Many ppl will be asymptomatic carriers for a long time before the leukemia can actually develop** |
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Life Cycle of HTLV-1.
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1)Interaction of the surface glycoptn of the virus with the receptor: Glucose Transporter
2)Early phase: fusion of lipid bilayer, partial uncoating, reverse transcription, nuclear transport, integration 3) Late Phase: Transcription of integrated proviral DNA, RNA processing and transport to the cytoplasm, transation and mb localization, assembly, budding/release, maturation |
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What does the HTLV genome look like?
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5' end---U3-R-U5-gag-pol-env-Tax-U3-R-U5--- 3' End
(C-terminal also contains a ew accessory genes important in expression of the protein) |
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What is in the U3 at the 5' end?
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Tax Respnse Elements (TRE)
-Regions to which the Tax ptn inteacts and upregulates transcription from the LTR -100-1000 fold inc in mRNA production |
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How does Tax interact with LTR?
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Interaction btw Tax and LTR is indirect
-Tax interfaces with cellular TF (interacts with CREB ptns) and increases their affinity by binding TREs, which upregulates transcription from the integrated proviral DNA |
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How many mRNAs are generated from HTLV?
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3 mRNAs
1) Full length RNA genome: codes for Gag, Pol, Protease -Needs 2 framshifts to make the Pol and the protease -2X as much structural ptn made as enzymatic ptns 2) Single-spliced mRNA (4kDA): used to generate Env ptns (TM and SU) -Splicing gets rid of most of teh Gag and Pol ptns, as well aspckging seq 3) Doubly spliced mRNA: get Tax/Rex -Encodes using dif reading frames to particular ptns |
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What is Rex for?
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Rex mediates the export of full length and singly spliced mRNA out of the nucleus and into the cytoplasm
-If you alter Rex, don't get transport to the cytoplasm and .: don't get any translation |
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Which cells can HTLV transform? Which cells can HTLV infect?
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-Transforms CD4+ cells only
-Infects many cells since a lot of cells have glucose transporters |
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What role does Tax play in leukemogenesis?
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-Activates celluar TF and signalling paths which activate both viral and cellular gene transcription (i.e. cell genes involved in T-cell growth)
-Tax induces T-cell activation and proliferation through an IL-2 autocrin loop (IL-2 is a T-cell growth factor that is essential for stimulation of T-cell prolif. IL-2 Autocrine loop, in addition to upregulation of alpha subunit of IL-2 by Tax causes a continuous stimnulatory loop that cause T-cell prolif) -Tax can interface with ptns to induce G1-S phase transition -Tax inhibits host cell DNA repair mechanisms, so cells accumulate mutations |
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What are the 3 stages to developing ATL from HTLV-1?
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1) Infection
2) IL-2 dependent growth phase: polyclonal T-cell proliferation (takes place in early phase of transformation). this is dependent n the IL-2 auto/paracrine loop 3) IL-2 independent growth phase: emergence of monoclonal leukemic T-cells. These cells emerge from a single T-cell clone that has grown out, accumulated mutations and IL-2 independence |
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Is shortcircuiting the IL-2 autocrine loop effective at stopping T-cll proliferation?
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Not really, since eventually, the infected cells will reach the IL-2 independent growth phase
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What happens to the T-cells in ATL?
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-Proliferation leads to Hyper-lobulated nuclei in T-cells (mostly CD4+ and 25+)
-This is cuz of accumulation of mutations that prevent the cells from undergoing proper mitosis -in late stage of ATL: Monoclonal integration og HTLV-1 provirus in tumour cells |
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Describe the organization of Tax.
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-Has CREB binding domain(CREB=cAMP respone element ptns)
-Middle region dimerizes with NF-kB TFs -Region at C-term that is imp for transactivation |
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Which genes are involved in activtion of gene expression by Tax?
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-Activating Txn Factor/CREB (leucine zipper ptns)
-CREB binding ptn (CBP) and p300 -NF-kB -Serum Response Factor (SRF) |
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How does Tax affect these TFs?
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1) Inc TF dimerization --> active forms
2) Inc nuclear localization of the TF |
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What happens when Tax bind CBP?
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-Preferential transcription of the viral genome
-Tax competes with cellular genes for bind CBP through the CBP KIX domain -Get altered gene expression HTLV-1 infected cells: genes for HTLV-1 replication and pathogenesis are favored |
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What is NF-kB? How is it activated?
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Family of immunoregulatory TF (exist in almost all cells in latent form, in the cytoplasm)
-Held in inactive form by IkB (inhibitor) -When IkB is P in response to a cellular signal, it's targetted for prteasomal degradation -DNA binding subunit of NF-kB would then be free and it can go to the nucleus, where it can activate genes |
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How does Tax interact with NF-kB path?
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-Can interact with DBD of NF-kB
-Can interface with IKK, the complex which leads to the P of IkB End result is it increase T-cell activation |
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Basics of Tax:
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-binds cellular TF and targets them to specific promoters
-acts as a molecular bridge to bring TFs bound to DNA in close proximity to transcriptional coactivators -these interactions result in preferential activation of genes regulated by Tax-interacting partners -> ATF/CREB; CBP: viral genome/LTR transcription -> NF-kB/p300: immune and inflammatory paths, cell proliferation -> SRF -> cell proliferation |
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What clinically characterizes HTLV1?
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**Abnormal and elevated T-lymphocytes (flowered, convuluted T-cells) + prominent eosinophilia**
also lymphadenopathy, hyperalcemia of bones, renal failure, skin lesions... -HTLV-1 infection can also indirectly cause other diseases via induction of immunodeficiencies |
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What are the clinical phases of ATL?
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1) Pre-ATL: no clinical signs for decades. Virus present, low T-cell activation, but many T-cells prolif
2) Smoldering: largely undiagnosed, less agressive, 5% abnormal T cells, skin lesions, normal WBC count. > 24 months 3) Chronic: Less agressive, prominent lesions, normal WBC count, 5% abnormal T-cell, modest bone marrow/visceral involvement. >24 months 4) Lymphoma: skin lesions, 5% abnormal T-cells, visceropathy, IL-2 independent, ATL is monoclonal, ineffective treatment. 10 months 5) Acute: Very aggressive, elevated WBC count, prominent skin lesions, >5% abnormal T-cells, visceropathy, hyperalcemia. 6 months |
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How do you treat ATL?
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Combination of AZT and interferon, but virus will eventually develop resistance
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Keep in mind, ATL:
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-Aggressive and fatal leukemia of CD4+ cells
-Long latency period = decades -4 clinical stages (not including pre-ATL): Smoldering, Chronic, Lymphoma, Acute -Usually only go see a doctor at acute or lymphoma stage and by that point, its too late -Acute ATL is the most severe |
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What is HAM characterized by?
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-**Infiltation of infected T-cells into the liver**
-Progressive demyelination of motor neurons in the spinal cord -spasticity |
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Pathogenicity of HAM?
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-Autoimmune model: HTLV-1 infection activates autoreactive T-cells which migrate to the nervous system and recognize antigens on CNS cells and destroy them
-Direct Immune model: HTLV-1 persistent infection and activation in the CNS leads to tissue destruction -Bystander Damage model Infected T-cells from blood flow into the CNS. They release a lot of growth factors, cytokines, inflammatory molec, causing inflammation rxn which destroys healthy CNS tissue |
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Keep in mind about HAM:
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-Chronic neurodegenerative syndrome
-Demylination of motor neurons -Long latency period -3 possible methods for explaining pathogenicity: Autoimmune, Direct, Bystander models -Other genetic/env't factors may contribute to ATL and HAM |
