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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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Dendritic cell dc targeting lentivector as a new hiv vaccine platform l.jpg

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 l.jpg

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.


Develop a dc targeting lenti vaccine l.jpg

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


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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).


Outline5 l.jpg

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.


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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


Slide7 l.jpg

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)


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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)


Outline9 l.jpg

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.


Develop dc targeting lentivector based hiv vaccine l.jpg

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)

……


Dc targeting lentivaccine elicited strong t cell and antibody responses to gag l.jpg

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)


Dc targeting lentivaccine induced multi functional cd4 and cd8 t cell responses to gag l.jpg

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)


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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)


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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.


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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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