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. 2008 May;38(5):1231-7.
doi: 10.1002/eji.200738011.

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

Denise Mirano-Bascos  1 , Magdalena Tary-Lehmann, Samuel J Landry
Affiliations

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

Denise Mirano-Bascos et al. Eur J Immunol. 2008 May.

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.

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Figures

Figure 1
Figure 1. Majority of the immunodominant epitopes in humans are found in the outer domain
Helper T-cell epitope mapping via IFN-γ ELISPOT shows that majority of immunodominant epitopes to gp120 lie in the outer domain, in or adjacent to regions of high sequence variability. The conventional domain structure of gp120 is illustrated at the top of the figure. The domain boundaries are aligned with the bar graph so that the diagram indicates the location of each peptide in the gp120 domain structure. Immunodominance patterns are the same when either (A) the number of IFN-γ producing cells or (B) the number of individuals with a positive response to a particular peptide is taken into account. (B) Stacked bars show the number and identity of the individuals that respond to each peptide. Responses to the inner domain, are almost unique in each human studied and are not significantly correlated with previous mouse data, indicating that the response in this domain may be influenced by MHC II specificity. (C) T-cell proliferation assays revealed a similar helper T-cell epitope immunodominance pattern in mice.
Figure 2
Figure 2. Helper T-cell epitopes are found adjacent to flexible and variable segments of gp120
(A) The epitope mapping data (empty bars) is superimposed on the graph of the average B-value for the corresponding peptide (solid line). (B) The Pearson correlation coefficient (r) between the two data sets was calculated for offsets that spanned the range of −20 to +20 in five-residue steps. A maximum correlation was observed when the outer domain data (solid circles) was offset by -12 residues from the B-factor data, indicating that epitopes in the outer domain are found an average of 12 residues toward the C-terminal of peaks of flexibility. (C) The epitope data (empty bars) was also compared to the average sequence entropy for each peptide (solid line). (D) Calculation of the Pearson correlation coefficients (r) revealed a maximum correlation (r2) at an offset of +5 for the inner domain (solid squares) and an offset of -11 for the outer domain. These results indicate that epitopes in the inner domain are found an average of 5 residues toward the N-terminal of conserved regions of the protein while those in the outer domain are found an average of 11 residues toward the C-terminal of peaks of sequence variability. No significant correlations were found for the whole protein (empty circles). Asterisks indicate correlation values with a p-value ≤ 0.05
Figure 3
Figure 3. Antigen structure affects processing and presentation of helper T-cell epitopes against gp120
Proposed models for the processing and presentation of helper T-cell epitopes in the outer domain (A) and inner domain (B). Details for each model are found in text. Structured regions of the outer domain are represented with black rectangles while structured regions of the inner domain are represented by black ovals. Flexible regions are represented by thick black lines and proteolyzed sections are represented by thick dashed lines. Proteolytic enzymes ( formula image), MHC II molecules ( formula image) and HLA-DM ( formula image ) are also shown.
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References

    1. WHO/UNAIDS. UNAIDS/WHO AIDS Epidemic Update: December 2006. Paperback. World Health Organization/UNAIDS; Geneva: 2006.
    1. Kuroda MJ, Schmitz JE, Charini WA, Nickerson CE, Lifton MA, Lord CI, Forman MA, Letvin NL. Emergence of CTL Coincides with Clearance of Virus During Primary Simian Immunodeficiency Virus Infection in Rhesus Monkeys. The Journal of Immunology. 1999;162:5127–5133. - PubMed
    1. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA. Control of Viremia in Simian Immunodeficiency Virus Infection by CD8+ Lymphocytes. Science. 1999;283:857–860. - PubMed
    1. Schmitz JE, Johnson RP, McClure HM, Manson KH, Wyand MS, Kuroda MJ, Lifton MA, Khunkhun RS, McEvers KJ, Gillis J, Piatak M, Lifson JD, Grosschupff G, Racz P, Tenner-Racz K, Rieber EP, Kuus-Reichel K, Gelman RS, Letvin NL, Montefiori DC, Ruprecht RM, Desrosiers RC, Reimann KA. Effect of CD8+ Lymphocyte Depletion on Virus Containment after Simian Immunodeficiency Virus SIVmac251 Challenge of Live Attenuated SIVmac239{Delta}3-Vaccinated Rhesus Macaques. The Journal of Virology. 2005;79:8131–8141. - PMC - PubMed
    1. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. The Journal of Virology. 1994;68:6103–6110. - PMC - PubMed

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