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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 blood titer (log10 pfu) LCMV-viremia control or nAb escape S1 S2 S3 7 6 5 4 S5 S6 S7 S8 3 2 1 0 S7 6 nAb titer (log2 x 20) 50 100 150 S8 200 nAb against: WE V1 V2 V3 V4 V5 V6 5 4 3 2 1 0 0 100 200 0 100 200 days after infection with 2x106pfu LCMV-WE (i.v.) Ciurea, Hunziker et al. B Ab • • • • T • Control-elim. intracell parasites also in solid organs • regulate longterm IgG • cause imunopathology (negative selection) Prevent penetration IgA systemic neutr.-opson.IgM/G adoptive transferable IgG IgM 1-2d, regulated by Ag-dose and structure (no negative selection) reverse genetic glycoprotein exchange between LCMV and VSV Pinschewer, de la Torre et al. rLCMV/INDG glycoprotein:IND-G LCMV glycoprotein: LCMV-GP rVSV/LCMV-GP glycoprotein: LCMV-GP VSV-IND glycoprotein:IND-G Only VSVG expressing viruses induce a neutralizing antibody response VSV-IND neutralization rLCMV/INDG neutralization 12 10 8 6 4 2 <1 12 10 8 6 4 2 <1 3 8 14 20 time after infection (days) 3 8 14 20 time after infection (days) LCMV-ARM neutralization rVSV/LCMV-GP neutralization 12 10 8 6 4 2 <1 12 10 8 6 4 2 <1 3 8 14 20 time after infection (days) 3 8 14 20 time after infection (days) total Ig 2x10 4 PFU rLCMV/INDG i.v. 2x10 4 PFU LCMV i.v. 2x10 4 PFU VSV-IND i.v. 2x10 4 PFU rVSV/LCMV-GP i.v. 2x10 7 PFU rVSV/LCMV-GP i.v. IgG LCMVHIS WEN-3 mAb Neutralising Ab: GP structure early: TH independent IgM, germline high affinity / avidity late: immunosuppression ? affinity maturation? Hypergammaglobulinemia vs. neutralizing antibodies 15 control anti CD8 6 CD8 -/- 5 control anti CD8 4 CD8 -/- 10 5 0 0 10 20 30 40 50 time after infection (days) Recher, Lang, Hunziker 2004 60 Neutralising antibodies 8 7 Neutralising titer (log 2) X 10 20 Neutralising antibodies Neutralising titer (log 2) X 10 Serum Immunglobulins (% of total serum proteins) Hypergammaglobulinemia 3 2 6 5 4 2 1 1 <1 <1 0 10 20 30 40 time after infection (days) 50 60 WE anti CD4 (1 :100) WE 3 0 10 20 30 40 time after infection (days) 50 60 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 CD4 T cells. • Mechanisms of B cell competition? (Cytokine receptor competition? Anatomic competition in germinal centers? Competition for anti-apoptotic cytokines?). Memory vs. Protection First infection kills host: no memory needed Host survives first infection: memory not necessary Why autoimmune disease in humans mostly via antibodies? Why >> ! Why all vaccines that function protect via neutr. antibodies? No protection by Memory B cells but protection by immune serum in _/_ IFN-aBR against VSV Anti-VSV neutr. AB % Survivors VSVIND immune spleen cells T+B <1: 40 0 LCMV immune spleen cells <1: 40 0 VSVIND Ab < 1 : 2500 100 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 persistent virus from mother Poliomyelitis – age distribution in Massachusetts 1912 – 1952 Years 1912-1916 1930-1934 1948-1952 Percent Percent 0 – 4 years 5 – 9 years 70 28 18 18 38 27 Percent 10+ years 12 34 55 Modified from: Nathanson,N. Am J Epidemiol 1979; 110:672-692. Memory / Pregnant Female • Academic: earlier + higher (AG –) • Immune against cytopathic infections otherwise abortions / malformations • MHC-incompatibility – offspring / mother • Maternal antibodies attenuate acute infections physiological 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 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) H. Hengartner E. A. L. M. U. Battegay Ciurea Hunziker Recher Steinhoff B. Odermatt Th.Leist K. Lang D. Pinschewer J. de la Torre IMMUNITY • “innate resistance“ > 95 % • • • • Ab in eggs protective memory via Ab (vaccines) TB: no vaccine autoimmunity > 30 y, female > male 5 : 1