Both humoral and cellular immunity against HIV and other pathogens depend on antigen-specific CD4+T cell responses directed against peptides presented in MHC class II antigen presenting proteins. Often these CD4+T-cell responses are focused on only a few immunodominant regions of naturally processed antigens. Therefore the ability to manipulate CD4+T-cell epitope immunodominance would create an opportunity to enhance immunity and to direct the immune response to conserved antigen sequences. Previous work shows that immunodominant regions occur adjacent to and on the C-terminal side of locally unstable segments of an antigen's three-dimensional structure. We hypothesize that such a pattern is due to preferential proteolytic processing at unstable sites followed by presentation of the C-terminal cleavage product. Inherently, such a hypothesis suggests that it should be possible to focus the CD4+T cell response on particular epitopes by inserting flexible segments adjacent to such epitopes within a target protein. We will test this hypothesis by analyzing the immune response against recombinant HIV gp 120 proteins which have been engineered to contain flexible loops. Enhanced proteolytic cleavage in the inserted loops should increase presentation of the adjacent epitopes and therefore in crease the epitope-specific CD4+T cell response. The effectiveness of loop insertion will be evaluated for three different sites in gp120. The magnitude and direction, with respect to Th1 vs. Th2, of immune responses will be measured by cytokine expression profiles for CD4+T cells from mice immunized with modified gp120 proteins and restimulated with either gp120 or each of a series of peptides spanning the gp120 sequence. Immune responses to the different immunogens will be compared in terms of antibody titers and CD8+ cytolytic T lymphocyte activity against gp120 and the peptide series.
| Landry, Samuel J (2008) Three-dimensional structure determines the pattern of CD4+ T-cell epitope dominance in influenza virus hemagglutinin. J Virol 82:1238-48 |
| Dai, G; Steede, N K; Landry, S J (2001) Allocation of helper T-cell epitope immunodominance according to three-dimensional structure in the human immunodeficiency virus type I envelope glycoprotein gp120. J Biol Chem 276:41913-20 |
| Landry, S J (2000) Helper T-cell epitope immunodominance associated with structurally stable segments of hen egg lysozyme and HIV gp120. J Theor Biol 203:189-201 |
