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Your logo. Natural control of HIV infection is associated with an isotype switched IgG antibody response to HIV Gag antigens in patients with 'non-protective' HLA-B alleles.

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  1. Your logo Natural control of HIV infection is associated with an isotype switched IgG antibody response to HIV Gag antigens in patients with 'non-protective' HLA-B alleles Martyn A French1, Rob J Center2, Kim M Wilson3, Ibrahim Fleyfel1, Sonia Fernandez1, Anna Schorcht2, Ivan Stratov2, Marit Kramski2, Stephen J Kent2, Anthony D Kelleher4 1. University of Western Australia, Perth, Australia 2. University of Melbourne, Melbourne, Australia 3. NRL, Melbourne, Australia 4. University of New South Wales, Sydney, Australia

  2. Immune control of HIV infection • CD8+ T cells and ‘protective’ HLA-B molecules (HLA-B*5701,-B2705, -B*14+Cw0802, -B*52) • NK cells (KIR and HLA-Bw4 or HLA-C) • Plasmacytoid dendritic cells • Antibodies • - Antibody-dependant cell-mediated cytotoxicity? • - Antibodies to Gag proteins? • - IgG2 antibodies?

  3. Diversification of antibody responses through immunoglobulin isotype switching TFH APRIL, BAFF, TGF-β, IL-10 IL-21 IFN-g IL-4 IgM IgG Subclasses IgE IgA IgG3 IgG1 IgG2 IgG4 Abbas et al. 2007

  4. Functional characteristics of IgG2 antibodies • • Polysaccharide antigens induce a predominantly IgG2 antibody response • Preferential binding to FcgRIIa • Deglycosylation of Fc region does not decrease binding to FcgRIIa • • Covalent dimerisation • Dominant IgG subclass in plasma immune complexes

  5. Patients and Methods • HIV Patients • 32 HIV controllers, including 14 elite controllers • 21 non-controllers with RNA >10,000 cps/mL and • CD4+ T cell count <100/mL • Methods • IgG1 and IgG2 Abs to HIV proteins by WB assay • IgG1 and IgG2 Abs to gp140 Env protein and rp55 • by ELISA • NK cell-mediated ADCC activity to gp140 Env • protein and Env and Gag peptides • Sequenced-based HLA typing on genomic DNA

  6. IgG1 antibodies to all HIV proteins, except gp41, are higher in HIV controllers P = 0.002 P < 0.001 P = 0.006 P < 0.001 P < 0.001 P = 0.440 P = 0.001

  7. Gag antigensdominate in the IgG2 antibodyresponseagainst HIV P = 0.014 P = 0.034 P = 0.045

  8. IgG2 antibodies to rp55 wereonlydetected in HIV controllers 1.2 IgG2 1.0 0.8 OD450 0.6 IgG1 anti-rp55 IgG2 anti-rp55 0.4 0.2 controllers non controllers neg P=0.09 P=0.14 0.6 IgG1 0.5 0.4 OD450 0.3 0.2 0.1 0 controllers non controllers neg

  9. IgG1 and IgG2 antibodies to gp140 Envproteindid not differentiatecontrollers and non-controllers IgG1 anti-gp140 Env protein IgG2 anti-gp140 Env protein P = 0.12 P = 0.34 non-controllers Endpoint titer (log10) Endpoint titer (log10) controllers non-controllers controllers non-controllers

  10. HIV controllersexhibithigher ADCC activity to gp140 Envprotein ADCC activity against gp140 Env protein was significantly higher in elite controllers than non-controllers (p=0.03)

  11. Antibody responses to HIV proteins in controllers without or with ‘protective’ HLA-B alleles # = HLA-B*57, -B*27, -B*52, B*14+Cw0802

  12. IgG2 antibodies to p24 are higher in HIV controllerswho do not carry HLA-B*57 IgG1 anti-p18 IgG1 anti-p32 IgG2 anti-p24 IgG2 anti-p18

  13. High-level IgG2 antibodies to one or more Gag protein (p18, p24, rp55) are mostcommon in HIV controllers not carrying ‘protective’ HLA-B alleles p=0.016 and 0.004 for trend

  14. Summary and Conclusions • • IgG2 antibodies to HIV Gag proteins may contribute to control of HIV infection • Preferential binding to FcgRIIa (major FcgR on pDCs) • Deglycosylation of Fc does not decrease binding to FcgRIIa • Phagocytosis-enhancing antibodies (bacteria, ?viruses) • Such antibodies might enhance innate responses to • HIV and/or adaptive immune responses to Gag • Strategies for vaccination with HIV Gag proteins might include enhancement of IgG isotype switching

  15. Induction of innate responses to HIV and/or adaptive responses to Gag by pDC and isotype-switched IgG antibodies: a hypothesis IFN-a and IFN-l Interferon-stimulated genes pDC-dependant NK cell activation TLR7 IRF-7 IgG2 Pro-inflammatory cytokines NFkB Gag + RNA FcgRIIa IgG1 MHC I MHC II X IgG3 CD8+ T cell CD70 = Endosomes B cell CD4+ T cell French MA, 2012 (unpublished)

  16. Control of HIV replication was better in patients possessing ‘high affinity’ FcgRIIa genotypes who produced IgG2 anti-p24 after vaccination with FPV/Gag-Pol/IFN-g DNA P=0.002 for FC recipients (o) P=0.0001 for all patients French MA et al. AIDS2010;24:1983-90

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