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Volume 6 Supplement 3

AIDS Vaccine 2009

P04-44. Generation of antibody responses to HIV-1 membrane proximal external region (MPER) antigen

Background

Immune responses to HIV-1 rarely generate broadly cross-reactive, neutralizing antibodies (NAb). Some NAbs are polyreactive and bind self-antigens, suggesting that effective humoral responses to some HIV-1 antigens are constrained by tolerization of NAb B cells.

Methods

The human HIV-1 NAb 2F5 was used to identify human and mouse self-antigens that cross-react with the gp41 MPER. Mouse B cells were generated absent the tolerizing environment of bone marrow (BM) in sequential cultures of non-adherent progenitor cells containing rIL-7, and later, rBAFF. RAG1-deficient mice were reconstituted with culture derived (CD) B and T cells (CD-RAG mice); 4 wks later serum immunoglobulin and autoantibody were quantified. CD-RAG and control mice were immunized with HIV-1 gp-41 MPER antigen in alum adjuvant; germinal center (GC) and antibody responses were determined 2 weeks after primary or boost immunizations.

Results

The 2F5 NAb binds to nuclear antigens in both uninfected human and mouse cells. BM and CD transitional B cells are enriched for reactivity to self and to an MPER antigen. Sera of CD-RAG and control mice have similar IgM/IgG serum levels but autoantibody titers are greatly elevated in CD-RAG animals. MPER antigen was weakly immunogenic in C57BL/6 mice, but MPER immunization of CD-RAG mice elicited strong (4-fold higher) GC responses and ~30-fold more MPER IgG antibody.

Conclusion

The 2F5 NAb binds to phylogenetically conserved nuclear antigens, consistent with the hypothesis that HIV-1 evades humoral immunity by exploiting immunological tolerance. We show that transitional B cells generated in vitro are enriched for autoreactive cells which survive and reconstitute serum antibody in vivo. Immunization of autoimmune CD-RAG mice with an MPER antigen results in significantly higher GC and antibody responses compared to intact controls. The CD-RAG mouse is a novel model for investigating ''forbidden'' humoral responses to HIV-1 antigens.

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Correspondence to TM Holl.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Holl, T., Kuraoka, M., Liao, D. et al. P04-44. Generation of antibody responses to HIV-1 membrane proximal external region (MPER) antigen. Retrovirology 6, P72 (2009). https://doi.org/10.1186/1742-4690-6-S3-P72

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Keywords

  • Antibody Response
  • Germinal Center
  • Nuclear Antigen
  • Humoral Response
  • Intact Control