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GKA deel 2 college 2

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  • 1. HIV-AIDS epidemiologie 2006
    • HIV –infected
      • ‘ Prevalence’
    • AIDS positive
    AIDS ribbon in China, July 2006
  • 2. Epidemiology 2005 UNAIDS http://data.unaids.org/pub/GlobalReport/2006/2006GR-PrevalenceMap_en.pdf
  • 3. Epidemiology 2005 UNAIDS http://data.unaids.org/pub/GlobalReport/2006/2006GR-PrevalenceMap_en.pdf
  • 4. Epidemiology 2005 UNAIDS http://data.unaids.org/pub/GlobalReport/2006/2006GR-PrevalenceMap_en.pdf
  • 5. Epidemiology 2005 UNAIDS http://data.unaids.org/pub/GlobalReport/2006/2006GR-PrevalenceMap_en.pdf Swaziland: 33% geinfecteerd! 2005
  • 6. Epidemiology 2005 UNAIDS http://data.unaids.org/pub/GlobalReport/2006/2006GR-PrevalenceMap_en.pdf Swaziland: 33% geinfecteerd! 2005  Stabilisation in South America and Africa?
  • 7. Epidemiology 2005 UNAIDS http://data.unaids.org/pub/GlobalReport/2006/2006GR-PrevalenceMap_en.pdf Swaziland: 33% geinfecteerd! 2005  Stabilisation in South America and Africa? Aug 2006: 40x10 6 persons with HIV/AIDS 20x10 6 persons died (In Netherlands: 11.000 infected)
  • 8. Treat Everyone Now? A 'Radical' Model to Stop HIV's Spread
    • Immediate treatment lowers viral load decrease HIV incidence
      • J. Cohen, Science 322 (2008) 1453
  • 9. The molecular biology of the AIDS virus Haseltine and Wong-Staal Sci Am. 259-4, 1988, 34-42
    • 2-10 yr after infection
      • flaring up of virus
      • decrease CD4-cells
      •  opportunistic infections
      •  death
    • Primary infection
      • flu-like symptoms
      • viremie
      • within weeks: virus disappears
        • but not completely
          • =set-point
    • Virus everywhere
      • blood, lymph nodes, brain,
  • 10. Names and abbreviations
    • The virus
    • HIV
    • Diameter 100 nm
    • H uman i mmuno-deficiency v irus
      • hiv-virus???
    • 9500 nt
      • adeno 50,000
      • polio 4000 nt
    • + stranded ss RNA
    • 2 strands/virion
    • The disease
    • AIDS
    • a cquired i mmuno- d eficiency s yndrome
  • 11. Structure of HIV www.lifehouseproductions.com
    • CA=Ca=p24: capsid
    • NC=p9, nucleocapsid
    • IN: integrase
    • Lipid: lipid
    • MA=p17: matrix
    • RT, reverse transcriptase
    • PR: protease
    • HLA=MHC
    • SU=p120=env: surface glycoprotein
    • TM=gp41: transmembrane
  • 12. Life cycle of HIV Haseltine and Wong-Staal Expression phase + -
    • Binding-fusion
    • Reverse transcription
    • Integration
    • Processing- maturation
    Infection phase Chemokine receptor CD4 Env Processing maturation Uncoating Reverse transcription Budding Microtubule Pre-integration complex Genomic RNA Protease Nef ssRNA Nuclear import Translation Rev Splicing Rev Linear DNA 5’LTR 3’LTR Fusion Transcription RT cDNA flap Vpr MA IN Rev Tat Vpu Vpr Nef Vif Tat RNA polII
  • 13. Binding and fusion of HIV to a target cell Walker and Burton, Science 320, 2008, 760-764
  • 14. Reverse transcriptase has no proofreading
    • Reverse transcriptase incorporates wrong nucleotide 1:10,000
      • Once every genome
      • As all RNA polymerases!
    • Cause of
      • Evolution
        • Heeney et al., Science 2006
      • Drug resistance
        • Bartlett and Moore, Sci Am 1998
      • Problems with vaccine design
        • Nabel, Nature 2001
      • Immunological escape
        • Nowak and McMichael, Sci Am 1993,
        • Cohen, Science 1993, 1260, 1261
    Added 270208: From www.tulane.edu /.../WWW/224/Replication224.html
  • 15.
    • Primers
      • tRNA Lys3
      • Ppt
      • Cppt
        • Polypurine tract
        • Resists RNase
        • Primes 5’ synthesis
    • PBS= Primer binding site
    Reverse transcriptase Abbink and Berkhout 2007 T.E.M. Abbink, B. Berkhout. HIV-1 reverse transcription: close encounters between the viral genome and a cellular tRNA. Adv. in Pharmacology. HIV-1: Molecular Biology and Pathogenesis: Viral Mechanisms, 2007, 55, 99-135 + + 5’ 3’ 3’ 5’
  • 16.
    • Primers
      • tRNA Lys3
      • Ppt
      • Cppt
        • Polypurine tract
        • Resists RNase
        • Primes 5’ synthesis
    • PBS= Primer binding site
    Reverse transcriptase Abbink and Berkhout 2007 T.E.M. Abbink, B. Berkhout. HIV-1 reverse transcription: close encounters between the viral genome and a cellular tRNA. Adv. in Pharmacology. HIV-1: Molecular Biology and Pathogenesis: Viral Mechanisms, 2007, 55, 99-135 + + + 5’ 3’ 3’ 5’
  • 17.
    • Primers
      • tRNA Lys3
      • Ppt
      • Cppt
        • Polypurine tract
        • Resists RNase
        • Primes 5’ synthesis
    • PBS= Primer binding site
    Reverse transcriptase Abbink and Berkhout 2007 T.E.M. Abbink, B. Berkhout. HIV-1 reverse transcription: close encounters between the viral genome and a cellular tRNA. Adv. in Pharmacology. HIV-1: Molecular Biology and Pathogenesis: Viral Mechanisms, 2007, 55, 99-135 + + + + 5’ 3’ 5’ 3’ 5’ 3’
  • 18.
    • Primers
      • tRNA Lys3
      • Ppt
      • Cppt
        • Polypurine tract
        • Resists RNase
        • Primes 5’ synthesis
    • PBS= Primer binding site
    Reverse transcriptase Abbink and Berkhout 2007 T.E.M. Abbink, B. Berkhout. HIV-1 reverse transcription: close encounters between the viral genome and a cellular tRNA. Adv. in Pharmacology. HIV-1: Molecular Biology and Pathogenesis: Viral Mechanisms, 2007, 55, 99-135 + + + + + 5’ 3’ 5’ 3’ 5’ 3’
  • 19.
    • Primers
      • tRNA Lys3
      • Ppt
      • Cppt
        • Polypurine tract
        • Resists RNase
        • Primes 5’ synthesis
    • PBS= Primer binding site
    Reverse transcriptase Abbink and Berkhout 2007 T.E.M. Abbink, B. Berkhout. HIV-1 reverse transcription: close encounters between the viral genome and a cellular tRNA. Adv. in Pharmacology. HIV-1: Molecular Biology and Pathogenesis: Viral Mechanisms, 2007, 55, 99-135
    • RT has 3 enzymatic functions
    • RNA-dependent DNA polymerase
    • RNAseH
    • DNA-dependent DNA polymerase
    + + + + + 5’ 3’ 5’ 3’ 5’ 3’
  • 20. Reverse transcriptase, part 2 Abbink and Berkhout 2007, Adv Pharmacol 55, 99-135 + Except for ppt and Cppt
  • 21. Reverse transcriptase, part 2 Abbink and Berkhout 2007, Adv Pharmacol 55, 99-135 + Except for ppt and Cppt cppt ppt
  • 22. Reverse transcriptase, part 2 Abbink and Berkhout 2007, Adv Pharmacol 55, 99-135 + Except for ppt and Cppt
  • 23. Reverse transcriptase, part 2 Abbink and Berkhout 2007, Adv Pharmacol 55, 99-135 + Except for ppt and Cppt
  • 24. Reverse transcriptase, part 2 Abbink and Berkhout 2007, Adv Pharmacol 55, 99-135 + Except for ppt and Cppt
  • 25. Reverse transcriptase, part 2 Abbink and Berkhout 2007, Adv Pharmacol 55, 99-135 + Except for ppt and Cppt
  • 26. Circular model of RT Cristofari et al., 2002, thanks to Abbink for ref.
    • Cristofari et al., 2002, EMBO J 21, 4368-4379
    • As described for a retrotransposon Ty1
      • Uses tRNA i Met
    Sarafianos and Arnold, Science 322 (2008) 1059-1060
  • 27. Is integration random?
    • PIC: pre-integration complex
    • Integration not random
      • Retroviruses prefer genes over non-gene DNA
    • A: murine leukemia virus
      • PIC binds transcription factors
    • B: HIV
      • Prefers an unknown component of transcription complex
    • C: Avian leukosis-sarcoma virus
      • Prefers a chromatin protein
    From: Engelman, PNAS, 102, 2005, 1275-1276 Unknown? The transcriptional coactivator lens epithelium-derived growth factor (LEDGF)/p75 acts as a chromatin tethering factor for HIV-1 integrase protein, determining … J. Biol. Chem. 279, (2004 ) 55570-55577,
  • 28. ATM: possible target for drugs? Daniel & Pomerantz, Nature Cell Biol 7, 2005, 452-453
    • During integration dsDNA break
    • Role DNA PK, ATM, ATR
    • KU-55933 inhibits ATM
      • Drug?
    • Directed against host!
  • 29. Three possibilities after integration