Antigen structure influences helper T‐cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120

Abstract

The development of an effective vaccine against HIV/AIDS has been hampered, in part, by a poor understanding of the rules governing helper T-cell epitope immunodominance. Studies in mice have shown that antigen structure modulates epitope immunodominance by affecting the processing and subsequent presentation of helper T-cell epitopes. Previous epitope mapping studies showed that the immunodominant helper T-cell epitopes in mice immunized with gp120 were found flanking flexible loops of the protein. In this report, we show that helper T-cell epitopes against gp120 in humans infected with HIV are also found flanking flexible loops. Immunodominant epitopes were found to be located primarily in the outer domain, an average of 12 residues C-terminal to flexible loops. In the less immunogenic inner domain, epitopes were found an average of five residues N-terminal to conserved regions of the protein, once again placing the epitopes C-terminal to flexible loops. These results show that antigen structure plays a significant role in the shaping of the helper T-cell response against HIV gp120 in humans. This relationship between antigen structure and helper T-cell epitope immunodominance may prove to be useful in the development of rationally designed vaccines against pathogens such as HIV.Key words: Antigen processing Á Helper T lymphocyte Á HIV envelope protein gp120 Á MHC class II Á Protein structure IntroductionOver the past 25 years, great strides have been made in the area of HIV/AIDS research. Much is now known about the biology and pathogenesis of the virus. In spite of this, HIV/AIDS continues to be a major health problem worldwide. In 2006, there were approximately 4.3 million new HIV cases, 400 000 more cases than in 2004, bringing the global total of people living with HIV to 39.5 million [1]. This number reflects the increase of HIV cases in every region of the world, suggesting that the epidemic is far from declining. In order to reverse this trend, an effective vaccine against HIV must be developed.Studies in humans and non-human primates have shown that the CD8 + cytotoxic T lymphocyte (CTL) response is essential to the control of viremia [2][3][4][5][6]. Neutralizing antibody has also been shown to aid in the maintenance of low viral loads, presumably through the prevention of viral transmission from cell to cell [7][8][9]. CD4 + helper T cells are required for the induction and maintenance of both of these effector mechanisms [10][11][12][13][14][15][16][17][18]. Therefore, the ideal vaccine against HIV must be able to activate these three arms of the immune response in order to confer protection against infection and disease progression. Helper T-cell activation begins when an immature CD4 + T cell encounters an antigen-presenting cell (APC) displaying a peptide bound to an MHC class II molecule (pMHCII). This contact between the CD4 + T cell and the pMHCII complex initiates a signaling cascade that leads to the maturation of the helper T cell. Although every sequence within a protein antigen can poten...

Comprehensive Analysis of Contributions from Protein Conformational Stability and Major Histocompatibility Complex Class II-Peptide Binding Affinity to CD4+Epitope Immunogenicity in HIV-1 Envelope Glycoprotein

“…In a sample of seven HIV ϩ subjects on antiretroviral therapy, the dominant epitopes of gp120 occurred on the C-terminal flanks of conformationally unstable gp120 segments, which we proposed was due to proteolytic cleavage in the unstable segment and preferential loading of the N-terminal segment of the C-terminal cleavage product (21). In a recent study of 93 untreated HIV ϩ subjects, promiscuously dominant epitopes were identified in Env sequences 30 to 46, 88 to 105, and 207 to 224, which correspond to peptides 1, 6, and 19 in the present study, respectively (11).…”

“…In HIV gp120, CD4 ϩ epitopes cluster adjacent to the variable loops, a pattern that has been identified in gp120-immunized BALB/c and CBA mice, as well as in HIV-infected persons (21)(22)(23). Since this dominance pattern occurs in the context of multiple MHC-II alleles, we attributed it to mechanisms of antigen processing.…”

“…All four immunogens shared epitopes in peptides 7, 43, and 44. The most remarkable changes in linear epitopes caused by disulfide deletions (difference of two or more mice) were the loss of epitopes at peptides 17, 19, and 20 in all three variants and the appearance of linear epitopes at peptides 21,22,24,30, and 47 in gp120dss298.…”

Influence of Disulfide-Stabilized Structure on the Specificity of Helper T-Cell and Antibody Responses to HIV Envelope Glycoprotein gp120

“…Dominant epitopes were located in the outer domain, an average of 12 residues C-terminal to flexible loops. In the less immunogenic inner domain, epitopes were found an average of five residues N-terminal to conserved regions of the protein, once again placing the epitopes C-terminal to flexible loops (30). These results suggested that antigen structure plays a significant role in the shaping of the helper T-cell response against HIV gp120 in both mice and humans.…”

“…This was rationalized by the fact that flexible loops more readily conform to protease active sites and therefore are preferentially cleaved by proteases during antigen processing (10,14,15). Helper T-cell epitopes of gp120 in humans infected with HIV were also found flanking flexible loops (30). Dominant epitopes were located in the outer domain, an average of 12 residues C-terminal to flexible loops.…”