Todd M. Allen 1 and David I. Watkins1
1Wisconsin 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 developing vaccines designed to induce virus-specific CTL responses. Various macaque species, most notably the rhesus macaque, have been used extensively to study AIDS virus pathogenesis and vaccine efficacy. As a result of these studies a number of SIV and SHIV CTL epitopes, and their restricting MHC class I molecules, have been identified. Accurate definition of these CTL epitopes, however, is critical both to the development of vaccines as well as to the construction of MHC class I tetrameric complexes which have revolutionized our ability to measure CTL responses to individual CTL epitopes. In the list provided below, only the Mamu-A*01 restricted CTL epitopes have been optimally defined through the use of peptide dilutions and knowledge of Mamu-A*01's peptide binding motif. The other epitopes listed in Table I have been identified through the use of overlapping peptides, however, their optimal lengths have yet to be determined. In Table II additional CTL epitopes are listed for which the restricting MHC class I molecules have yet to be identified. Furthermore, the majority of these epitopes have only been mapped using overlapping 20mer peptides. It will be important to define both the restricting MHC class I molecule of these epitopes and their optimal length if they are to be considered for use in vaccination trials or tetramer construction. The expansion of this list will be very important to studies designed to examine the role of CTL in AIDS virus infections and the effectiveness of CTL-based vaccines. Please contact us with any additional contributions to this list.
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 Table 1: Defined CTL Epitopes with Known Restricting MHC class I Molecules Virus Protein Epitope Restricting MHC Genbank Reference Class I Allele1 Acc.No. SIVmac251 Gag CTPYDINQM Mamu-A*01 U50836 Miller, et al. 1991 Allen, et al. 1998 SHIV Env YAPPISGQI Mamu-A*01 U50836 Egan, et al. 1999 SHIV Pol STPPLVRLV Mamu-A*01 U50836 Egan, et al. 1999 SIVmac251 Env YNLTMKCR Mamu-A*02 U50837 Watanabe, et al. 1994 HIV-1 Env KPCVKLTP Mamu-A*08 Voss, et al. 1996 SIVmac251 Env EITPIGLAP2 Mamu-B*01 U42837 Yasutomi, et al. 1995 HIV-1 Env NNLLRAIEA Mamu-B*12 Voss, et al. 1996 SIVmac32H-J5 Gag SVDEQIQWM Mafa -A*02 Geretti, at al. 1997 1MHC Class I allele designations: Rhesus macaque (Macaca mulatta) Mamu; cynomolgus macaque (Macaca fascicularis) Mafa 2We have been unable to detect responses to this CTL epitope in Mamu-B*01 defined, SIV infected rhesus macaques (Allen, et al. unpublished observations) Table 2: CTL Epitopes without Defined Restricting MHC class I Molecules Virus Protein Epitope Restricting MHC Reference Class I Allele SIVmac251 Nef GLEGIYYSAR unknown Mortara, et al. 1998 SIVmac239 Env CNKSETDRW unknown Erickson, et al. 1994 SIVmac251 Nef DWQDYTSGPGIRYPK unknown Bourgault, et al. 1992 SIVmac251 Nef LRAMTYKLAIDMSHFI unknown Bourgault, et al. 1992 SIVmac251 Nef GIRYPKTFGWLWKLV unknown Bourgault, et al. 1992 SIV Gag SYVDRFYKSLRAEQTD- unknown Gotch, et al. 1993 AAYK SIVmac251 Env YCTLYVTVFY unknown Allen, et al. unpublished Env SCTRMMETQTSTWFGF- unknown Allen, et al. unpublished NGTR Env GRDNRTIISL unknown Allen, et al. unpublished Env RRPGNKTVLPVTIMSG- unknown Allen, et al. unpublished LVFH
1. 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.
2. 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.
3. Egan, M. A., M. J. Kuroda, G. Voss, J. E. Schmitz, W. A. Charini, C. I. Lord, M. A. Forman, and N. L. Letvin. 1999. Use of MHC Class I/peptide Tetramers to Quantitate CD8+ CTL Specific for Dominant and Non-dominant Viral Epitopes in Simian-Human Immunodeficiency Virus-infected Rhesus Monkeys. Submitted.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.