The goal of this new R21 proposal is to develop a pro-inflammatory and non-tolerogenic HIV vaccine delivery system based on the dendritic cell targeting anti-DEC-205 antibody. The success of anti-DEC-205 as a stimulator of strong inflammatory immune responses depends on co-administration of non-specific dendritic cell maturation factors. In their absence, anti-DEC-205 induces antigen-specific tolerance rather than immunity. We hypothesize that regulatory T-cell epitopes contained in anti-DEC-205 promote a tolerogenic reaction that is only overcome through the co-administration of non-specific immuno-stimulators. This hypothesis is based on our discovery of a set of natural regulatory T-cell epitopes derived from human immunoglobulins that induce tolerance by stimulating regulatory T cells. We have verified experimentally that these epitopes cause antigen-specific expansion of regulatory T cells and suppress inflammatory immune responses. We propose to develop a modified pro-inflammatory and non-tolerogenic anti-DEC-205 antibody. We expect that modification of regulatory T-cell epitopes will significantly diminish tolerogenicity, enabling use of anti-DEC-205 as a stand-alone HIV antigen delivery system that obviates the dangers associated with non-specific activation of the immune system. We will de-tolerize anti-DEC-205 by epitope modification using the process we developed to reduce immunogenicity of protein therapeutics. We will substitute key amino acids in the regulatory T-cell epitopes with those that are experimentally shown to interfere with MHC binding. We will then (1) produce a set of antibody variants recombinantly conjugated to HIV Gag, (2) identify de-tolerizing mutations that do not interfere with dendritic-cell targeting, and (3) and evaluate variants for reduced tolerogenicity, as well as for enhanced Gag immunogenicity. Finally, we will produce and characterize the immunogenicity of a de-tolerized anti-DEC-205-based HIV vaccine composed of immunogenic consensus sequences.

Public Health Relevance

This project will develop an improved delivery vehicle for HIV vaccine components. Immune-dampening portions of the delivery vehicle will be silenced so that potent and effective immune responses can be raised against HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21AI078800-02S2
Application #
8145044
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Pensiero, Michael N
Project Start
2008-09-30
Project End
2011-08-31
Budget Start
2009-09-27
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$243,561
Indirect Cost
Name
Epivax, Inc.
Department
Type
DUNS #
135531015
City
Providence
State
RI
Country
United States
Zip Code
02903