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MULTIFACETED INTERACTIONS OF RETROVIRUSES WITH THE COMPLEMENT SYSTEM

MULTIFACETED INTERACTIONS OF RETROVIRUSES WITH THE COMPLEMENT SYSTEM. H. Stoiber Vienna, 19.07.2010. V irologie. Schematic overview of Immune responses upon viral Infections. Vienna, 19.07.2010. Consequences of complement activation. Phagocytosis. Antigen - Presentation.

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MULTIFACETED INTERACTIONS OF RETROVIRUSES WITH THE COMPLEMENT SYSTEM

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  1. MULTIFACETED INTERACTIONS OF RETROVIRUSES WITH THE COMPLEMENT SYSTEM H. Stoiber Vienna, 19.07.2010 Virologie

  2. Schematic overview of Immune responses upon viral Infections Vienna, 19.07.2010

  3. Consequences of complement activation Phagocytosis Antigen - Presentation Vienna, 19.07.2010 Immune complexes T cell CR3 Infected cell Pathogens M CR1 CR2 DCs MAC Lysis Opsonisation C3a C5a Complement activaton Chemotaxis Inflammation C3a C5a Y Y Y Cellactivation Y iC3b C3d C3a C5a Increased Permeability Trapping B cells FDCs APCs Granulocytes Basophils Mast cells Granulocytes Basophils Mast cells DCs

  4. Ex vivo detection of HIV in LT of infected Patients Vienna, 19.07.2010 (Schacker et al. 2000)

  5. Complement-dependent Trapping of HIV in the LT Vienna, 19.07.2010 Kacani et al. JV

  6. Relationship between Trapping and AIDS Vienna, 19.07.2010 Species Virus Source Trapping AIDS-like Symptoms African Green Monkey SIVagm no no Sooty mangabeySIVsm no no Rhesus Monkey SIVmacyes yes Chimpanzees SIVchp/HIV-1 no no Human HIV-1 yes yes

  7. Consequences of Complement activation Phagocytosis Antigen - Presentation Vienna, 19.07.2010 Immune complexes T cell CR3 Infected cells Pathogens M CR1 CR2 DCs MAC Lysis Opsonisation C3a C5a Complement activation Chemotaxis Inflammation C3a C5a Y Y Y Cellactivation Y iC3b C3d C3a C5a Trapping Increased Permeability B cells FDCs APCs Granulocyte Basophils Mast cells Granulozytes Basophils Mast cells DCs

  8. In vitro Prime-Boost experiments: protocol Vienna, 19.07.2010 Loading of DCs withSEB, HIV, HIV-C  autologous, unstimulated CD8+ T cells (Prime) Boost of primed CD8+ T cells with Ag-loaded DCs (3x) (all cells from the same donor) Data-Acquisition of Prime-Boost Experiments Proliferation-assays (CFSE staining) IFN-g assays (ELISA, Secretions-assay) Test on Specificity and Functionality of in vitro generated CTLs (Tetramer, degranulation, antiviral activity)

  9. Proliferation of HIV-C-DC-primed CD8+ T cells (7 Donors 5 Viral strains) Vienna, 19.07.2010 Tetramer-staining Bánki et a., PLoS Path., 2010 Apr 29;6(4):e1000891.

  10. antiviral response of HIV-C-DC-primed CD8+ T cells (5 Donors, 4 viral Strains) Vienna, 19.07.2010 Bánki et a., PLoS Path., 2010 Apr 29;6(4):e1000891.

  11. env: Recombination deletion, insertion F-MuLV F-SFFV (replication competent helper-virus) LTR LTR LTR gagpol env LTR gagpol env gp55 Erythroleukemia induced by Friend Virus (FV) in mice Vienna, 19.07.2010 • Helper virus, F-MuLV (murine leukemia virus),  is responsible for growth of the virus complex. • F-MuLV can only produce lymphomas if injected into neonatal mice. • F-SFFV (spleen focus-forming virus) is defective/interfering virus that expresses gp55 env protein that binds to EpoR to produce erythroblastosis; has no oncogene; 1st Stage Expansion of erythroblasts in spleen due togp55 2nd Stage Malignant transformation of erythroblasts

  12. Enhanced FV-infection of C3-deficient Mice correlates with lower Frequencies of FV-specific CTLs. Vienna, 19.07.2010 5 4 3 2 1 0 0.0025 8 6 4 2 0 10 8 6 4 2 0 0.0119 0.0088 CD11c+ %infectedcells 40 30 20 10 0 0.0405 CD8+ %FVgag tetramer+CD43+ CD8+ %FVgag tetramer+ %infected cells B6 4dpi B6 control B6C3-/- 4dpi B6C3-/- control B6 7dpi B6 7dpi B6 control B6 control B6C3-/- 7dpi B6C3-/- 7dpi B6C3-/- control B6C3-/- control B6 7dpi B6 control B6C3-/- 7dpi B6C3-/- control Bánki et a., PLoS Path., 2010 Apr 29;6(4):e1000891.

  13. Consequences of Complement activation Phagocytosis Antigen - Presentation Vienna, 19.07.2010 Immune complexes T cell CR3 Infected cells Pathogens M CR1 CR2 DCs MAC Lyse Opsonisation C3a C5a Complement activation Chemotaxis Inflammation C3a C5a Y Y Y Cellactivation Y iC3b C3d C3a C5a Increased Permeability Trapping B Zellen FDCs APCs Granulocyte Basophils Mast cells Granulocyte Basophils Mast cells DCs

  14. Complement activation, MAC and Opsonisation Vienna, 19.07.2010 Complement Activation P P P CD55 fH factor I factor I P C3 + CR1 + factor H + MCP C3b iC3b C3d MAC P Host cells are protected from CML by Regulators of the Complement system LYSE Why are intact and infectious viruses in the serum? CD59

  15. Cell infected with Retroviruses “budding” gp120/41 complex MHC-I MHC-II DAF CD59 fH + Serum + Antibody + Serum budding of HIV Vienna, 19.07.2010 Efficient Virolyse Inefficient Virolyse Stoiber et al. JEM Stoiberet al, Nat. Med.

  16. Factor H in Detail heparin binding heparinbinding C3b binding catalyticregion C3b/c binding C3b/d binding FactorH 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Expression 2 7 13 18 19 20 Cross-link tomAb SCR18 SCR19 SCR20 SCR13 SCR7 SCR2 Vienna, 19.07.2010 Complement-specific Part Pathogen-specific Antibody Binding site is distinct from the enzymatic active site

  17. NMS NMS+Ab-SCR Input virus D = 9ct units eq. 3 logs In vitro Lysis of FV by complement in the Presence of the Constructs Vienna, 19.07.2010 NMS+Ab Igepal Patent: WO 2008/135237 A1

  18. Infectious Centers in the Spleen Vienna, 19.07.2010 Reduction of the viral titers at about 3logs Patent: WO 2008/135237 A1

  19. Summary I Vienna, 19.07.2010 Y HIV-C CR2 Trapping of HIV in vivo is mainly dependent on Complement-CR interactions; thus, Complement shows responsible for maintaining the largest viral reservoir in HIV-infected individuals Follicular Dendritic Cells

  20. Summary II Vienna, 19.07.2010 IFN-g antiviral Activity high HIV-C/FV-C CD8 TC Infected cells HIV/FV antiviral Activity low Complement is a natural adjuvant for the induction of retrovirus-specific CTLs

  21. retrovirus C‘ C‘ Y C C C‘ C‘ Y Y Y Y Y Y Y Y retrovirus C C constructs Summary III Vienna, 19.07.2010 X Y X X Y Y AIM: Reconstitute CML by Pathogen-specific constructs Putative Targets beside HIV: Other enveloped-Viruses, Bacteria

  22. Acknowledgements Vienna, 19.07.2010 Institute of Applied Microbiology, Boku, Vienna G. Stiegler H. Katinger Bernhard-Nocht-Institute, Hamburg K. Tenner-Racz P. Racz Department of Medicine, Eppendorf, Hamburg J. van Lunzen Rockefeller University, New York R. Steinman Institute of Biochemistry, Epalingen H. Archa-Orbea German Primate Center, Göttingen C. Stahl-Henning Institute of Virology, Essen U. Dittmer Institute of Med. Virology, Bochum K. Überla Institute of Immunology, Helsinki S. Jokiranta Section of Immunology ,St. Gallen B. Ludewig Retroviral Immunology Section, Hamilton Kim Hasenkrug Ron Messer Institute of Virology, Zürich A. Trkola

  23. THINK OPSONIZED! Thankyou ! Vienna, 19.07.2010 Section of Virology, Innsbruck Doris Wilflingseder WilfriedPosch Zoltan Banki AsimEjaz VerenaOberhauser ChristophAmmann Georg Huber Brigitte Müllauer Heribert Stoiber Section of Microbiology, Innsbruck Cornelia Lass-Flörl Dept. of Haematology, Innsbruck Günter Gastl EU, , MFI FFG Österreichischen Förderungsgesellschaften

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