Despite aggressive treatment protocols based on powerful drug combinations currently available, the incidence of HIV-1 infection continues to rise and it is now pandemic in many of the developing nations. These protocols are highly successful at reducing viral loads, even to undetectable levels, but they do not eliminate quiescent reservoirs of viral infection. Thus, treatments must be lifelong, are costly, and are accompanied by significant toxic side effects. This situation requires consideration of alternative strategies and it remains a consensus in the biomedical research community that an immunotherapeutic vaccine will eventually provide the most effective, affordable long-term approach to halting the spread of HIV/AIDS. The collective experience to date is that HIV is immunogenic; it provokes an immune response in most infected individuals, but this immune response must be considered to be ineffective. Current vaccine trials consist of immunization with attenuated native virus, virion proteins or their peptide fragments; so far none have proven to be successful. Stronger immunogens are required. One approach not yet tried involves alterations of the peptide sequence of native viral T cell epitopes to create optimized, highly immunogenic peptide analogues that provoke strong T cell mediated immunity that eliminates viral infected cells in the body. MSI has developed the technology and provided proof-of-concept for screening combinatorial peptide libraries with T cell lines and clones having a clinically relevant specificity to identify panels of highly immunogenic peptides that are more effective in stimulating immune responses against the native peptide sequence.
The specific Aims are 1) to identify optimized mimic peptides for several HLA-A2 restricted epitopes of conserved HIV proteins; 2) assess their immunogenicity in HLA-A2 transgenic mice; and 3) explore strategies for further enhancement of immunogenicity. Ultimately, this peptide sequence information will be incorporated into a therapeutic/ prophylactic multi-epitope vaccine formulation based on multiple peptides, fusion proteins or DNA sequences in viral vectors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44DA015212-04
Application #
6916456
Study Section
Special Emphasis Panel (ZRG1-VACC (10))
Program Officer
Khalsa, Jagjitsingh H
Project Start
2001-09-30
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$748,571
Indirect Cost
Name
Mixture Sciences, Inc.
Department
Type
DUNS #
006119437
City
San Diego
State
CA
Country
United States
Zip Code
92121
Schaubert, Keri L; Price, David A; Salkowitz, Janelle R et al. (2010) Generation of robust CD8+ T-cell responses against subdominant epitopes in conserved regions of HIV-1 by repertoire mining with mimotopes. Eur J Immunol 40:1950-62
Blondelle, Sylvie E; Moya, Rosa; Schroder, Kim et al. (2009) Natural mutants of HIV CTL epitopes with enhanced immunogenicity as potential vaccine candidates. Adv Exp Med Biol 611:379-82
Blondelle, Sylvie E; Moya-Castro, Rosa; Osawa, Keiko et al. (2008) Immunogenically optimized peptides derived from natural mutants of HIV CTL epitopes and peptide combinatorial libraries. Biopolymers 90:683-94