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Dendritic Cell (DC)-targeting Lentivector as a New HIV Vaccine Platform

Dendritic Cell (DC)-targeting Lentivector as a New HIV Vaccine Platform Lili Yang, Ph.D. California Institute of Technology HVTN Conference November 19, Thursday, 2009 Seattle, WA Outline Introduce the DC-targeting Lentivector;

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Dendritic Cell (DC)-targeting Lentivector as a New HIV Vaccine Platform

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  1. Dendritic Cell (DC)-targeting Lentivector as a New HIV Vaccine Platform Lili Yang, Ph.D. California Institute of Technology HVTN Conference November 19, Thursday, 2009 Seattle, WA

  2. Outline • Introduce the DC-targeting Lentivector; • Discuss the potential of DC-targeting Lentivector as a vaccine; • Develop DC-targeting lenti-vector as a new HIV vaccine.

  3. Develop a DC-targeting Lenti-vaccine Lentivector: HIV-1 based self-inactivating vector Palucka AK., et. al., Immunol. Rev.220:129-150 (2007). DC receptor for targeting: DC-SIGN Dendritic Cell Specific ICAM-3 (Intracellular Adhesion Molecules 3) -Grabbing Nonintegrin

  4. Targeting Lentivector to DC Through DC-SIGN DC-SIGN: Dendritic Cell Specific ICAM-3 (Intracellular Adhesion Molecules 3) -Grabbing Nonintegrin Yang L., et. al., Nat. Biotechnol.26: 326-334 (2008).

  5. Outline • Introduce the DC-targeting Lentivector; • Discuss the potential of DC-targeting Lentivector as a vaccine; • Develop DC-targeting lenti-vector as a new HIV vaccine.

  6. LTR Prom Antigen LTR DC-targeting lentivector expressing a model tumor antigen has been demonstrated to be a potent cancer vaccine in a mouse tumor model (Yang L., et. al., Nat. Biotechnol.26: 326-334. 2008) The full potential of this new vaccine platform is still under exploring

  7. LTR Prom OVA LTR LTR Prom TfR OVA LTR Designer Antigen Can Direct DCs to Mount CD8-prone or CD4-prone T Cell Immune Response TfR: membrane anchor domain of transferrin receptor Lentiviral construct FKOVA Lentiviral construct FMOVA Surface-bound form of antigen encoded by lentiviral construct FMOVA rapidly endocytosed Cytoplasmic form of antigen encoded by lentiviral construct FKOVA Immunize OT2 Tg Mice Yang L., Baltimore D. & Wang P. (unpublished data)

  8. LTR Prom TfR OVA IRES CD40L LTR IgG Endpoint Titer (Log Dilution) membrane +CD40L native membrane Inclusion of CD40L as a “Genetic Adjuvant” in Lentivaccine to Improve Antibody Response Lentviral construct to contain CD40L Immunization Hypothesized mechanism for the role of CD40L to augment humoral immune response Yang L., Baltimore D. & Wang P. (unpublished data)

  9. Outline • Introduce the DC-targeting Lentivector; • Discuss the potential of DC-targeting Lentivector as a vaccine; • Develop DC-targeting lenti-vector as a new HIV vaccine platform.

  10. Develop DC-targeting Lentivector-based HIV Vaccine * DC-specific expression to reduce side effect! LTR Promoter HIV Antigen(s) IRES /2A Genetic Adjuvant LTR Immunization Combinatory Regimens (e.g. DNA prime) +/-Adjuvant(s) (TLR agonists …) HIV Antigen Design: Native v.s. Designer Ag Protein v.s. Epitopes CD8 v.s. CD4 type Ag Single v.s. Multiple Ags… DNA (over expression) SiRNA/MicroRNA (knockdown) Improve DC maturation: GM-CSF, IL-12, CD40L… Enhance DC function: B7,4-1BBL,CD40L… Modulate immune response: CD40L (Ab response) IL-7, IL-15 (T cell memory) IFN-r (Th1) IL-4 (Th2) ……

  11. DC-targeting Lentivaccine Elicited Strong T Cell and Antibody Responses to Gag Dai B., Yang L., Yang H., Hu B., Baltimore D. & Wang P. (unpublished data)

  12. DC-targeting Lentivaccine Induced Multi-functional CD4+ and CD8+ T Cell Responses to Gag Dai B., Yang L., Yang H., Hu B., Baltimore D. & Wang P. (unpublished data)

  13. DC-Targeting Lentivaccine Induced a Broad T Cell Response to Gag Dai B., Yang L., Yang H., Hu B., Baltimore D. & Wang P. (unpublished data)

  14. Future Work • Continue to optimize the DC-targeting lentivaccine in mice, aiming to induce the desired types of anti-HIV immune responses; • Test the potency of DC-targeting lentivaccine to protect SIV infection in NHP model.

  15. Acknowledgements Supported by: • National Institute of Allergy and Infectious Diseases (NIAID) • National Institutes of Health (NIH) • Division of AIDS (DAIDS) • U.S. Department of Health and Human Services (HHS) Center for HIV/AIDS Vaccine Immunology (CHAVI) # U19 AI067854-05 Bill & Melinda Gates Foundation Caltech Baltimore Lab David Baltimore Yang Yu Moni Kalwani USC Wang Lab Pin Wang Bingbing Dai Haiguang Yang Biliang Hu VRC, NIAID, NIH Dr. Gary Nabel FHCRC Dr. Juliana McElrath Dr. Larry Corey

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