This proposal will focus on the macromolecular assemblage approach to design and test HIV vaccine adjuvant formulations in a rational systematic, and chemically unambiguous manner. The macromolecular assemblage approach recently developed in our laboratory is a system of reconstituting various cellular components to mimic the whole organism that allows evaluation of their contribution to immunity and includes oligomeric peptide antigens on a scaffolding known as the multiple antigen peptide system (MAPS), lipid membrane-anchoring moieties, lipid matrices and lipid soluble adjuvants. It also allows the flexibility in presenting mixtures of peptide and protein antigens, including recombinant gpl2O, in liposomes or lipid matrices. MAPS with a built-in lipid membrane anchor (LipoMAPS) have been shown to be a B-cell mitogen, a cytokine inducer and a potent antigen-specific adjuvant. The immediate goal of this project is the development of lipoMAPS with gp 120 in liposomes as a novel and antigen-specific adjuvant formulation for vaccines against HIV- 1 and the long term goal is the development of an effective and clinically acceptable adjuvant formulation and vaccine against HIV-1.
The specific aims are: 1. Develop stable and effective molecular assemblage in liposomes and lipid matrices and test their efficacy in small animals for elicitation of humoral and cell-mediated immunities, including the stimulation of cytokines and CTLs. 2. Study the adjuvant effects of lipid anchors and synergism of extraneous lipophilic adjuvants in the macromolecular assemblage approach. 3. Test LipoMAPS with the entrapped recombinant gpl2O in the macromolecular assemblage as a novel and antigen-specific adjuvant in inducing type- and group-specific humoral responses as well as cell-mediated immunities. 4. Test efficacy of LipoMAPS in small animals to stimulate mucosal immunity. 5. Develop the molecular assemblage approach of presenting mixtures of B- and T-cell epitopes to overcome the antigen diversity of different HIV-1 isolates.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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AIDS and Related Research Study Section 1 (ARRA)
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Vanderbilt University Medical Center
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Tam, J P; Lu, Y A; Liu, C F et al. (1995) Peptide synthesis using unprotected peptides through orthogonal coupling methods. Proc Natl Acad Sci U S A 92:12485-9
Spetzler, J C; Tam, J P (1995) Unprotected peptides as building blocks for branched peptides and peptide dendrimers. Int J Pept Protein Res 45:78-85
Tam, J P; Spetzler, J C (1995) Chemoselective approaches to the preparation of peptide dendrimers and branched artificial proteins using unprotected peptides as building blocks. Biomed Pept Proteins Nucleic Acids 1:123-32
Spetzler, J C; Rao, C; Tam, J P (1994) A novel strategy for the synthesis of the cysteine-rich protective antigen of the malaria merozoite surface protein (MSP-1). Knowledge-based strategy for disulfide formation. Int J Pept Protein Res 43:351-8
Liu, C F; Tam, J P (1994) Peptide segment ligation strategy without use of protecting groups. Proc Natl Acad Sci U S A 91:6584-8
Vanage, G R; Jaiswal, Y K; Lu, Y A et al. (1994) Immunization with synthetic peptide segments of a sperm protein impair fertility in rats. Res Commun Chem Pathol Pharmacol 84:3-15
Nardelli, B; Haser, P B; Tam, J P (1994) Oral administration of an antigenic synthetic lipopeptide (MAP-P3C) evokes salivary antibodies and systemic humoral and cellular responses. Vaccine 12:1335-9
Huang, W; Nardelli, B; Tam, J P (1994) Lipophilic multiple antigen peptide system for peptide immunogen and synthetic vaccine. Mol Immunol 31:1191-9
Nardelli, B; Tam, J P (1993) Cellular immune responses induced by in vivo priming with a lipid-conjugated multimeric antigen peptide. Immunology 79:355-61
Nardelli, B; Lu, Y A; Shiu, D R et al. (1992) A chemically defined synthetic vaccine model for HIV-1. J Immunol 148:914-20

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