Todd M. Allen and David I. Watkins
Wisconsin Regional Primate Research Center, 1220 Capitol Court, Madison, WI 53715, USA
There is accumulating evidence to suggest a key role for CTL in the containment of HIV and SIV infections. As such, there is considerable interest in designing vaccines to induce virus-specific CTL responses. Various macaque species, most notably rhesus macaques of Indian origin, have been used extensively to study AIDS virus pathogenesis and vaccine efficacy. Unfortunately, until recently only a few SIV and SHIV CTL epitopes with their restricting MHC class I molecules had been identified. Virtually all of the epitope-specific studies conducted to date in the rhesus macaque have focused on responses to an SIV Gag CTL epitope (Gag181; CTPYDINQM) restricted by Mamu-A*01. However, it is becoming increasingly difficult for investigators to obtain sufficient numbers of Mamu-A*01 positive animals. Therefore, definition of new CTL epitopes will be critical to both vaccine development, and to construction of MHC class I tetrameric complexes which have revolutionized our ability to measure CTL responses to individual CTL epitopes [1--3].
In the updated list provided in this report, 28 new Mamu-A*01-restricted CTL epitopes have been added (Table I). These new epitopes were defined by scanning all SIV proteins using the Mamu-A*01 motif , by peptide binding studies [5--6], and through functional CTL and ELISPOT assays [7--8]. Fortunately, these new Mamu-A*01 epitopes are distributed throughout many different SIV proteins which should facilitate a broad range of studies. Applying this approach to defining multiple SIV-derived CTL epitopes for other rhesus MHC class I molecules will increase the utility of the SIV-infected rhesus macaque as an animal model for studying AIDS virus pathogenesis and vaccine efficacy.
Five newly defined SIV CTL epitopes have also been identified which are restricted by 4 other rhesus MHC class I molecules; Mamu-A*11, -B*03, -B*04, and -B*17 (Table I). These minimal, optimal epitopes were defined using CTL assays [9--10] and peptide binding assays  with dilutions of peptides of varying lengths. Hopefully, some of these MHC class I alleles will exist at sufficient frequencies to provide investigators access to additional animals for SIV CTL epitope-related studies, thus alleviating the current difficulties of obtaining sufficient MHC-defined animals. The identification of new SIV epitopes, restricted by high frequency MHC class I molecules, would broaden our ability to examine epitope-specific responses in SIV-infected macaques.
Additional CTL epitopes are also listed for which the restricting MHC class I molecules have yet to be identified (Table II). It will be important to eventually define both the optimal epitope length and restricting MHC class I molecule if they are to be used effectively in vaccination trials or tetramer construction. This updated list, which now contains a total of 39 SIV and SHIV CTL epitopes with known restricting MHC class I molecules, will be useful for both the development and testing of epitope-based vaccines and for monitoring responses to these epitopes in vaccinated and SIV-infected macaques.
If you are aware of additional epitopes which could be added to this listing, please contact:
Bette Korber Todd M. Allen David I. Watkins phone: 505-665-4453 608-265-3381 608-265-3380 fax: 505-665-3493 608-263-4031 608-263-4031 email: firstname.lastname@example.org email@example.com firstname.lastname@example.org
|Virus||Protein||Epitope||Restriction MHC class I Allele1||Genbank Acc. No.||Reference|
|Virus||Protein||Epitope||Restriction MHC class I Allele1||Reference|
Figure 1a. Gag CTL Epitopes
Figure 1b. Pol CTL Epitopes
Figure 1c. Env CTL Epitopes
Figure 1d. Nef CTL Epitopes
Figure 1e. Tat, Vif, Vpx, and Rev CTL Epitopes
1. Altman, J. D., P. A. H. Moss, P. J. R. Goulder, D. H. Barouch, M. G. McHeyzer-Williams, J. I. Bell, A. J. McMichael, and M. M. Davis. 1996. Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94--96.
2. Kuroda, M. J., J. E. Schmitz, D. H. Barouch, A. Craiu, T. M. Allen, A. Sette, D. I. Watkins, M. A. Forman, and N. L. Letvin. 1998. Analysis of gag-specific cytotoxic T lymphocytes in simian immunodeficiency virus-infected rhesus monkeys by cell staining with a tetrameric major histocompatibility complex class I peptide complex. Journal of Experimental Medicine 187:1373--1381.
3. Doherty, P. C. 1998. Update - Immunology - the Numbers Game For Virus-Specific CD8(+) T Cells. Science 280:227. 4. Allen, T. M., J. Sidney, M. F. Delguercio, R. L. Glickman, G. L. Lensmeyer, D. A. Wiebe, R. Demars, C. D. Pauza, R. P. Johnson, A. Sette, and D. I. Watkins. 1998. Characterization of the peptide binding motif of a rhesus MHC class I molecule (Mamu-A*01) that binds an immunodominant CTL epitope from simian immunodeficiency virus. Journal of Immunology 160:6062--6071.
5. Sette, A., A. Vitiello, B. Reherman, P. Fowler, R. Nayersina, W. M. Kast, C. J. Melief, C. Oseroff, L. Yuan, J. Ruppert, J. Sidney, M. F. del Guercio, S. Southwood, R. T. Kubo, R. W. Chesnut, H. M. Grey, and F. V. Chisari. 1994. The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. Journal of Immunology 153:5586--92.
6. Sette, A., J. Sidney, M. F. del Guercio, S. Southwood, J. Ruppert, C. Dahlberg, H. M. Grey, and R. T. Kubo. 1994. Peptide binding to the most frequent HLA-A class I alleles measured by quantitative molecular binding assays. Molecular Immunology 31:813--22.
7. Schmittel, A., U. Keilholz, and C. Scheibenbogen. 1997. Evaluation of the interferon-gamma ELISPOT-assay for quantification of peptide specific T lymphocytes from peripheral blood. Journal of Immunological Methods 210:167--74.
8. Miyahira, Y., K. Murata, D. Rodriguez, J. R. Rodriguez, M. Esteban, M. M. Rodrigues, and F. Zavala. 1995. Quantification of antigen specific CD8+ T cells using an ELISPOT assay. Journal of Immunological Methods 181:45--54.
9. Evans, D. T., P. Jing, T. M. Allen, D. H. OConnor, H. Horton, J. E. Venham, M. Piekarczyk, M. Dykhuzen, J. Mitchen, R. A. Rudersdorf, C. D. Pauza, R. E. Bontrop, R. DeMars, and D. I. Watkins. 1999. Definition of five new SIV CTL epitopes and their restricting MHC class I molecules: Effect on disease progression. Manuscript submitted.
10. Evans, D. T., D. H. O'Connor, P. Jing, D. J. L., J. Sydney, J. da Silva, T. M. Allen, H. Horton, J. E. Venham, R. A. Rudersdorf, C. D. Pauza, R. E. Bontrop, R. DeMars, A. Sette, A. L. Hughes, and D. I. Watkins. 1999. Virus-specific CTL responses select for amino acid variation in SIV Env and Nef. Nature Medicine 5:1270--1276.
11. Dzuris, J. L., J. Sidney, D. T. Evans, E. Appella, R. W. Chesnut, D. I. Watkins, and A. Sette. 2000. Conserved MHC class I peptide binding motif between humans and rhesus macaques. Journal of Immunology 164:283--291.
12. Allen, T. M., B. R. Mothe, J. Sidney, P. Jing, J. L. Dzuris, T. U. Vogel, D. H. O'Connor, J. D. Altman, D. I. Watkins, and A. Sette. 1999. CD8+ Lymphocytes from SIV-Infected Rhesus Macaques Recognize 27 Different Epitopes Bound by the Single MHC class I Molecule Mamu-A*01: Implications For Vaccine Design and Testing. Manuscript submitted.
13. Miller, M. D., H. Yamamoto, A. L. Hughes, D. I. Watkins, and N. L. Letvin. 1991. Definition of an epitope and MHC class I molecule recognized by gag-specific cytotoxic T lymphocytes in SIVmac-infected rhesus monkeys. Journal of Immunology 147:320--9.
14 Egan, M. A., M. J. Kuroda, J. E. Schmitz, W. A. Charini, C. I. Lord, M. A. Forman, and N. L. Letvin. 1999. Use of major histocompatibility complex class I/peptide/2M tetramers to quantitate CD8(+) cytotoxic T lymphocytes specific for dominant and nondominant viral epitopes in simian-human immunodeficiency virus-infected rhesus monkeys. Journal of Virology 73:5466--5472.
15. Furchner, M., A. L. Erickson, T. M. Allen, D. I. Watkins, A. Sette, P. R. Johnson, and C. M. Walker. 1999. The simian immunodeficiency virus envelope glycoprotein contains two epitopes presented by the Mamu-A*01 class I molecule. Journal of Virology 73:8035--8039.
16. Voss, G., and N. L. Letvin. 1996. Definition of human immunodeficiency virus type 1 gp120 and gp41 cytotoxic T-lymphocyte epitopes and their restricting major histocompatibility complex class I alleles in simian-human immunodeficiency virus-infected rhesus monkeys. Journal of Virology 70:7335--40.
17. Watanabe, N., S. N. McAdam, J. E. Boyson, M. S. Piekarczyk, Y. Yasutomi, D. I. Watkins, and N. L. Letvin. 1994. A simian immunodeficiency virus envelope V3 cytotoxic T-lymphocyte epitope in rhesus monkeys and its restricting major histocompatibility complex class I molecule Mamu-A*02. Journal of Virology 68:6690--6.
18. Geretti, A. M., E. G. Hulskotte, M. E. Dings, C. A. van Baalen, G. van Amerongen, and A. D. Osterhaus. 1997. CD8+ cytotoxic T lymphocytes of a cynomolgus macaque infected with simian immunodeficiency virus (SIV) mac32H-J5 recognize a nine amino acid epitope in SIV Gag p26. Journal of General Virology 78:821--4.
19. Yasutomi, Y., S. N. McAdam, J. E. Boyson, M. S. Piekarczyk, D. I. Watkins, and N. L. Letvin. 1995. A MHC class I B locus allele-restricted simian immunodeficiency virus envelope CTL epitope in rhesus monkeys. Journal of Immunology 154:2516--22.
20. Yamamoto, H., M. D. Miller, H. Tsubota, D. I. Watkins, G. P. Mazzara, V. Stallard, D. L. Panicali, A. Aldovini, R. A. Young, and N. L. Letvin. 1990. Studies of cloned simian immunodeficiency virus-specific T lymphocytes. Gag-specific cytotoxic T lymphocytes exhibit a restricted epitope specificity. Journal of Immunology 144:3385--91.
21. Bourgault, I., A. Venet, and J. P. Levy. 1992. Three epitopic peptides of the simian immunodeficiency virus Nef protein recognized by macaque cytolytic T lymphocytes. Journal of Virology 66:750--6.
22. Bourgault, I., F. Chirat, A. Tartar, J. P. Levy, J. G. Guillet, and A. Venet. 1994. Simian immunodeficiency virus as a model for vaccination against HIV. Induction in rhesus macaques of Gag- or Nef-specific cytotoxic T lymphocytes by lipopeptides. Journal of Immunology 152:2530--7.
23. Mortara, L., F. Letourneur, H. Gras-Masse, A. Venet, J. G. Guillet, and I. Bourgault-Villada. 1998. Selection of virus variants and emergence of virus escape mutants after immunization with an epitope vaccine. Journal of Virology 72:1403--10.
24. Mortara, L., H. Gras-Masse, C. Rommens, A. Venet, J. G. Guillet, and I. Bourgault-Villada. 1999. Type 1 CD4(+) T-cell help is required for induction of antipeptide multispecific cytotoxic T lymphocytes by a lipopeptidic vaccine in rhesus macaques. Journal of Virology 73:4447--4451.
25. Gotch, F., D. Nixon, A. Gallimore, S. McAdam, and A. McMichael. 1993. Cytotoxic T lymphocyte epitopes shared between HIV-1, HIV-2, and SIV. Journal of Medical Primatology 22:119--23.
26. Erickson, A. L., and C. M. Walker. 1994. An epitope in the V1 domain of the simian immunodeficiency virus (SIV) gp120 protein is recognized by CD8+ cytotoxic T lymphocytes from an SIV-infected rhesus macaque. Journal of Virology 68:2756--9.>