1887

Abstract

MHC-I-restricted cytotoxic responses are considered a critical component of protective immunity against viruses, including human immunodeficiency virus type 1 (HIV-1). CTLs directed against accessory and early regulatory HIV-1 proteins might be particularly effective; however, CTL epitopes in these proteins are rarely found. Novel artificial neural networks (ANNs) were used to quantitatively predict HLA-A2-binding CTL epitope peptides from publicly available full-length HIV-1 protein sequences. Epitopes were selected based on their novelty, predicted HLA-A2-binding affinity and conservation among HIV-1 strains. HLA-A2 binding was validated experimentally and binders were tested for their ability to induce CTL and IFN- responses. About 69 % were immunogenic in HLA-A2 transgenic mice and 61 % were recognized by CD8 T-cells from 17 HLA-A2 HIV-1-positive patients. Thus, 31 novel conserved CTL epitopes were identified in eight HIV-1 proteins, including the first HLA-A2 minimal epitopes ever reported in the accessory and regulatory proteins Vif, Vpu and Rev. Interestingly, intermediate-binding peptides of low or no immunogenicity (i.e. subdominant epitopes) were found to be antigenic and more conserved. Such epitope peptides were anchor-optimized to improve immunogenicity and further increase the number of potential vaccine epitopes. About 67 % of anchor-optimized vaccine epitopes induced immune responses against the corresponding non-immunogenic naturally occurring epitopes. This study demonstrates the potency of ANNs for identifying putative virus CTL epitopes, and the new HIV-1 CTL epitopes identified should have significant implications for HIV-1 vaccine development. As a novel vaccine approach, it is proposed to increase the coverage of HIV variants by including multiple anchor-optimized variants of the more conserved subdominant epitopes.

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2003-09-01
2021-03-07
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References

  1. Addo M. M., Altfeld M., Rosenberg E. S.. 9 other authors 2001; The HIV-1 regulatory proteins Tat and Rev are frequently targeted by cytotoxic T lymphocytes derived from HIV-1-infected individuals. Proc Natl Acad Sci U S A98:1781–1786
    [Google Scholar]
  2. Addo M. M., Altfeld M., Rathod A., Yu M., Yu X. G., Goulder P. J., Rosenberg E. S., Walker B. D.. 2002; HIV-1 Vpu represents a minor target for cytotoxic T lymphocytes in HIV-1-infection. AIDS16:1071–1073
    [Google Scholar]
  3. Altfeld M. A., Addo M. M., Eldridge R. L.. 12 other authors 2001a; Vpr is preferentially targeted by CTL during HIV-1 infection. J Immunol167:2743–2752
    [Google Scholar]
  4. Altfeld M. A., Livingston B., Reshamwala N.. 20 other authors 2001b; Identification of novel HLA-A2-restricted human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte epitopes predicted by the HLA-A2 supertype peptide-binding motif. J Virol75:1301–1311
    [Google Scholar]
  5. Andersen M. H., Tan L., Sondergaard I., Zeuthen J., Elliott T., Haurum J. S.. 2000; Poor correspondence between predicted and experimental binding of peptides to class I MHC molecules. Tissue Antigens55:519–531
    [Google Scholar]
  6. Berzofsky J. A.. 1993; Epitope selection and design of synthetic vaccines. Molecular approaches to enhancing immunogenicity and cross-reactivity of engineered vaccines. Ann N Y Acad Sci690:256–264
    [Google Scholar]
  7. Berzofsky J. A., Ahlers J. D., Derby M. A., Pendleton C. D., Arichi T., Belyakov I. M.. 1999; Approaches to improve engineered vaccines for human immunodeficiency virus and other viruses that cause chronic infections. Immunol Rev170:151–172
    [Google Scholar]
  8. Borrow P., Lewicki H., Hahn B. H., Shaw G. M., Oldstone M. B.. 1994; Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol68:6103–6110
    [Google Scholar]
  9. Buus S., Stryhn A., Winther K., Kirkby N., Pedersen L. O.. 1995; Receptor-ligand interactions measured by an improved spun column chromatography technique. A high efficiency and high throughput size separation method. Biochim Biophys Acta1243:453–460
    [Google Scholar]
  10. Buus S., Lauemoller S. L., Worning P.. 7 other authors 2003; Sensitive quantitative predictions of peptide-MHC binding by a ‘Query by Committee’ artificial neural network approach. . Tissue Antigens (in press)
    [Google Scholar]
  11. Carmichael A., Jin X., Sissons P., Borysiewicz L.. 1993; Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein–Barr virus in late disease. J Exp Med177:249–256
    [Google Scholar]
  12. Chouquet C., Autran B., Gomard E., Bouley J. M., Calvez V., Katlama C., Costagliola D., Riviere Y.. 2002; Correlation between breadth of memory HIV-specific cytotoxic T cells, viral load and disease progression in HIV infection. AIDS16:2399–2407
    [Google Scholar]
  13. Epstein H., Hardy R., May J. S., Johnson M. H., Holmes N.. 1989; Expression and function of HLA-A2.1 in transgenic mice. Eur J Immunol19:1575–1583
    [Google Scholar]
  14. Falk K., Rotzschke O., Stevanovic S., Jung G., Rammensee H. G.. 1991; Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature351:290–296
    [Google Scholar]
  15. Feltkamp M. C., Vreugdenhil G. R., Vierboom M. P., Ras E., van der Burg S. H., ter Schegget J., Melief C. J., Kast W. M.. 1995; Cytotoxic T lymphocytes raised against a subdominant epitope offered as a synthetic peptide eradicate human papillomavirus type 16-induced tumors. Eur J Immunol25:2638–2642
    [Google Scholar]
  16. Firat H., Tourdot S., Ureta-Vidal A.. 8 other authors 2001; Design of a polyepitope construct for the induction of HLA-A0201-restricted HIV 1-specific CTL responses using HLA-A*0201 transgenic, H-2 class I KO mice. Eur J Immunol31:3064–3074
    [Google Scholar]
  17. Gegin C., Lehmann-Grube F.. 1992; Control of acute infection with lymphocytic choriomeningitis virus in mice that cannot present an immunodominant viral cytotoxic T lymphocyte epitope. J Immunol149:3331–3338
    [Google Scholar]
  18. Gulukota K., Sidney J., Sette A., DeLisi C.. 1997; Two complementary methods for predicting peptides binding major histocompatibility complex molecules. J Mol Biol267:1258–1267
    [Google Scholar]
  19. Hanke T., McMichael A. J.. 2000; Design and construction of an experimental HIV-1 vaccine for a year-2000 clinical trial in Kenya. Nat Med6:951–955
    [Google Scholar]
  20. Human Retroviruses & AIDS 1998; A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences Los Alamos National Laboratory; New Mexico: Theoretical Biology and Biophysics Group;
    [Google Scholar]
  21. Hunziker I. P., Cerny A., Pichler W. J.. 1998; Who is right? Or, how to judge the disagreement about HLA restriction of Nef peptides. AIDS Res Hum Retroviruses14:921–924
    [Google Scholar]
  22. Kast W. M., Brandt R. M., Sidney J., Drijfhout J. W., Kubo R. T., Grey H. M., Melief C. J., Sette A.. 1994; Role of HLA-A motifs in identification of potential CTL epitopes in human papillomavirus type 16 E6 and E7 proteins. J Immunol152:3904–3912
    [Google Scholar]
  23. Kaul R., Dong T., Plummer F. A.. 12 other authors 2001; CD8+ lymphocytes respond to different HIV epitopes in seronegative and infected subjects. J Clin Invest107:1303–1310
    [Google Scholar]
  24. Kern F., Surel I. P., Brock C.. 9 other authors 1998; T-cell epitope mapping by flow cytometry. Nat Med4:975–978
    [Google Scholar]
  25. Klein M. R., van Baalen C. A., Holwerda A. M.. 7 other authors 1995; Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med181:1365–1372
    [Google Scholar]
  26. Korber B., Brander C., Haynes B., Koup R., Kuiken C., Moore J. P., Walker B. D., Watkins D. I.. (editors) 2000; HIV Molecular Immunology Los Alamos National Laboratory, New Mexico: Theoretical Biology and Biophysics;
    [Google Scholar]
  27. Koup R. A., Safrit J. T., Cao Y., Andrews C. A., McLeod G., Borkowsky W., Farthing C., Ho D. D.. 1994; Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol68:4650–4655
    [Google Scholar]
  28. McMichael A. J., Rowland-Jones S. L.. 2001; Cellular immune responses to HIV. Nature410:980–987
    [Google Scholar]
  29. Milik M., Sauer D., Brunmark A. P., Yuan L., Vitiello A., Jackson M. R., Peterson P. A., Skolnick J., Glass C. A.. 1998; Application of an artificial neural network to predict specific class I MHC binding peptide sequences. Nat Biotechnol16:753–756
    [Google Scholar]
  30. Nielsen H. V., Lauemoller S. L., Christiansen L., Buus S., Fomsgaard A., Petersen E.. 1999; Complete protection against lethal Toxoplasma gondii infection in mice immunized with a plasmid encoding the SAG1 gene. Infect Immun67:6358–6363
    [Google Scholar]
  31. Novitsky V., Rybak N., McLane M. F.. 13 other authors 2001; Identification of human immunodeficiency virus type 1 subtype C Gag-, Tat-, Rev-, and Nef-specific ELISPOT-based cytotoxic T-lymphocyte responses for AIDS vaccine design. J Virol75:9210–9228
    [Google Scholar]
  32. Pantaleo G., Demarest J. F., Schacker T.. 14 other authors 1997; The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia. Proc Natl Acad Sci U S A94:254–258
    [Google Scholar]
  33. Pascolo S., Bervas N., Ure J. M., Smith A. G., Lemonnier F. A., Perarnau B.. 1997; HLA-A2.1-restricted education and cytolytic activity of CD8+ T lymphocytes from β 2 microglobulin ( β 2m) HLA-A2.1 monochain transgenic H-2Db β2m double knockout mice. J Exp Med185:2043–2051
    [Google Scholar]
  34. Rammensee H. G., Friede T., Stevanoviic S.. 1995; MHC ligands and peptide motifs: first listing. Immunogenetics41:178–228
    [Google Scholar]
  35. Rodriguez F., Slifka M. K., Harkins S., Whitton J. L.. 2001; Two overlapping subdominant epitopes identified by DNA immunization induce protective CD8+ T-cell populations with differing cytolytic activities. J Virol75:7399–7409
    [Google Scholar]
  36. Rowland-Jones S. L., Nixon D. F., Aldhous M. C., Gotch F., Ariyoshi K., Hallam N., Kroll J. S., Froebel K., McMichael A.. 1993; HIV-specific cytotoxic T-cell activity in an HIV-exposed but uninfected infant. Lancet341:860–861
    [Google Scholar]
  37. Rowland-Jones S., Sutton J., Ariyoshi K.. 8 other authors 1995; HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nat Med1:59–64
    [Google Scholar]
  38. Rowland-Jones S. L., Pinheiro S., Kaul R.. 9 other authors 2001; How important is the ‘quality’ of the cytotoxic T lymphocyte (CTL) response in protection against HIV infection?. Immunol Lett79:15–20
    [Google Scholar]
  39. Santra S., Barouch D. H., Kuroda M. J.. 9 other authors 2002; Prior vaccination increases the epitopic breadth of the cytotoxic T-lymphocyte response that evolves in rhesus monkeys following a simian-human immunodeficiency virus infection. J Virol76:6376–6381
    [Google Scholar]
  40. Schafer J. R., Jesdale B. M., George J. A., Kouttab N. M., De Groot A. S.. 1998; Prediction of well-conserved HIV-1 ligands using a matrix-based algorithm, EpiMatrix. Vaccine16:1880–1884
    [Google Scholar]
  41. Seder R. A., Hill A. V.. 2000; Vaccines against intracellular infections requiring cellular immunity. Nature406:793–798
    [Google Scholar]
  42. Sette A., Buus S., Appella E., Smith J. A., Chesnut R., Miles C., Colon S. M., Grey H. M.. 1989; Prediction of major histocompatibility complex binding regions of protein antigens by sequence pattern analysis. Proc Natl Acad Sci U S A86:3296–3300
    [Google Scholar]
  43. Sette A., Vitiello A., Reherman B.. 8 other authors 1994; The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol153:5586–5592
    [Google Scholar]
  44. Shirai M., Arichi T., Nishioka M., Nomura T., Ikeda K., Kawanishi K., Engelhard V. H., Feinstone S. M., Berzofsky J. A.. 1995; CTL responses of HLA-A2.1-transgenic mice specific for hepatitis C viral peptides predict epitopes for CTL of humans carrying HLA-A2.1. J Immunol154:2733–2742
    [Google Scholar]
  45. Stryhn A., Pedersen L. O., Romme T., Holm C. B., Holm A., Buus S.. 1996; Peptide binding specificity of major histocompatibility complex class I resolved into an array of apparently independent subspecificities: quantitation by peptide libraries and improved prediction of binding. Eur J Immunol26:1911–1918
    [Google Scholar]
  46. van der Most R. G., Concepcion R. J., Oseroff C., Alexander J., Southwood S., Sidney J., Chesnut R. W., Ahmed R., Sette A.. 1997; Uncovering subdominant cytotoxic T-lymphocyte responses in lymphocytic choriomeningitis virus-infected BALB/c mice. J Virol71:5110–5114
    [Google Scholar]
  47. Walker B. D., Korber B. T.. 2001; Immune control of HIV: the obstacles of HLA and viral diversity. Nat Immunol2:473–475
    [Google Scholar]
  48. Wentworth P. A., Vitiello A., Sidney J., Keogh E., Chesnut R. W., Grey H., Sette A.. 1996; Differences and similarities in the A2.1-restricted cytotoxic T cell repertoire in humans and human leukocyte antigen-transgenic mice. Eur J Immunol26:97–101
    [Google Scholar]
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