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SIV and SHIV CTL Epitopes Identified in Macaques

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:	btk@t10.lanl.gov   tallen@primate.wisc.edu	watkins@primate.wisc.edu

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





References

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.

last modified: Fri Aug 10 14:02 2007


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