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HIV – FIV - LCMV

HIV – FIV - LCMV. Immune system + viruses Tricks of pers. V: T deletion / escape nAb delay / escape Re-encountered / persistent antigen maintains nAb (successful vaccines) and act. T (infection immunity: no vaccine) for protection. LCMV-viremia control or nAb escape. Ciurea, Hunziker et al.

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HIV – FIV - LCMV

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  1. HIV – FIV - LCMV • Immune system + viruses • Tricks of pers. V:T deletion / escapenAb delay / escape • Re-encountered / persistent antigen maintains nAb (successful vaccines) and act. T (infection immunity: no vaccine) for protection

  2. LCMV-viremia control or nAb escape Ciurea, Hunziker et al.

  3. Prevent penetration IgA • systemic neutr.-opson.IgM/G • adoptive transferable IgG • IgM 1-2d, regulated byAg-dose and structure(no negative selection) B Ab T • Control-elim. intracell parasites also in solid organs • regulate longterm IgG • cause imunopathology(negative selection)

  4. reverse genetic glycoprotein exchange between LCMV and VSV Pinschewer, de la Torre et al. rLCMV/INDG rVSV/LCMV-GP glycoprotein:IND-G glycoprotein: LCMV-GP LCMV VSV-IND glycoprotein: LCMV-GP glycoprotein:IND-G

  5. Only VSVG expressing viruses induce a neutralizing antibody response

  6. Neutralising Ab: GP structure early: TH independent IgM, germline high affinity / avidity late: immunosuppression ? affinity maturation?

  7. Hypergammaglobulinemia vs. neutralizing antibodies Hypergammaglobulinemia Neutralising antibodies Neutralising antibodies Recher, Lang, Hunziker 2004

  8. Conclusion: • Many nAb "specificities" control V, if "one" too slow/low: V-escape! • Hypergammaglobulinemia and polyclonal B cell activation compete with nAb responses and seem to depend upon amount of virus-specific CD4T cells. • Mechanisms of B cell competition? (Cytokine receptor competition? Anatomic competition in germinal centers? Competition for anti-apoptotic cytokines?).

  9. Memory vs. Protection Why autoimmune disease inhumans mostly via antibodies? First infection kills host:no memory needed Host survives first infection:memory not necessary Why >> !Why all vaccines that function protect via neutr. antibodies?

  10. No protection by Memory B cells but protection by immune serum in IFN-aBR_/_ against VSV Anti-VSV neutr. AB < 1 : 40 < 1 : 40 < 1 : 2500 % Survivors 0 0 100 VSVIND immune spleen cells T+B LCMV immune spleen cells VSVIND Ab

  11. Maintenance of protection 1. Agent persists: TB, leprosy, HIV, HCV, LCMV Herpes viruses crippled: measles? 2. Repetitive inf.: polio, bact. toxins 3. Antibody-antigen complex depots in lymph nodes and spleens

  12. persistent virusfrom mother

  13. Poliomyelitis – age distribution in Massachusetts 1912 – 1952

  14. Memory / Pregnant Female • Academic: earlier + higher (AG –) • Immune against cytopathic infectionsotherwise abortions / malformations • MHC-incompatibility – offspring / mother • Maternal antibodies attenuate acute infectionsphysiological vaccinations (incl. malaria, eggs) • Non-cytophatic infections transferred via placenta / at birth / after birth (LCMV, HCV, Herpes) • Resistance via T cells: HIV, HTV, TB Lepr. slow • "Emerging" infections

  15. Conclusions: Persistent infections numbers / variability • T cell control – immunopathology – "tolerance" • nAb essential (affinity maturation?) or escape • antigen maintains nAb titers and act. T cells (but immunopathology!) • All successful vaccines: nAb not successful: should (also) maintain act.T (not achieved yet)

  16. Battegay Ciurea Hunziker M. Recher U. Steinhoff Odermatt Th. Leist Lang Pinschewer J. de la Torre H. Hengartner

  17. IMMUNITY • “innate resistance“ > 95 % • Ab in eggs • protective memory via Ab (vaccines) • TB: no vaccine • autoimmunity > 30 y, female > male 5 : 1

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