SIV and SHIV CTL Epitopes Identified in Macaques
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 [4], 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 [11] 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: btk@t10.lanl.gov tallen@primate.wisc.edu watkins@primate.wisc.edu
Table I.Defined CTL Epitopes with Known Restricting MHC class I Molecules
| Virus | Protein | Epitope | Restriction MHC class I Allele1 | Genbank Acc. No. | Reference |
| Mamu-A Molecules | |||||
| SIVmac251 | Gag149-157 | LSPRTLNAW | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Gag181-189 | CTPYDINQM | Mamu-A*01 | U50836 | [4,13] |
| SIVmac251 | Gag254-262 | QNPIPVGNI | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Gag340-349 | VNPTLEEMLT | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Gag372-379 | LAPVPIPF | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Pol51-61 | EAPQFPHGSSA | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Pol143-152 | LGPHYTPKIV | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Pol147-155 | YTPKIVGGI | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Pol359-368 | GSPAIFQYTM | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Pol474-483 | IYPGIKTKHL | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Pol588-596 | QVPKFHLPV | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Pol621-629 | STPPLVRLV | Mamu-A*01 | U50836 | [12,14] |
| SIVmac251 | Pol692-700 | SGPKTNIIV | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Env235-243 | CAPPGYAL(L) | Mamu-A*01 | U50836 | [12,15] |
| SHIV-89.6 | Env431-439 | YAPPISGQI | Mamu-A*01 | U50836 | [14] |
| SIVmac251 | Env504-512 | ITPIGLAPT | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Env622-630 | TVPWPNASL2 | Mamu-A*01 | U50836 | [12] |
| SIVsmE660 | Env622-630 | TVPWPNETL2 | Mamu-A*01 | U50836 | [15] |
| SIVmac251 | Env728-736 | SSPPSYFQT | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Env729-738 | SPPSYFQTHT | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Env763-771 | SWPWQIEYI | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Tat28-35 | TTPESANL | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Vif14-22 | RIPERLERW | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Vif144-152 | QVPSLQYLA | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Vpx8-18 | IPPGNSGEETI | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Vpx39-48 | HLPRELIFQV | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Vpx102-111 | GPPPPPPPGL | Mamu-A*01 | U50836 | [12] |
| SIVmac251 | Rev87-96 | DPPTNTPEAL | Mamu-A*01 | U50836 | [12] |
| SHIV | Env99-106 | KPCVKLTP | Mamu-A*08 | [16] | |
| SIVmac251 | Env307-314 | YNLTMKCR | Mamu-A*02 | U50837 | [17] |
| SIVmac239 | Env497-504 | GDYKLVEI | Mamu-A*11 | [9--11] | |
| SIVmac32H-J5 | Gag242-250 | SVDEQIQWM | Mafa-A*02 | [18] | |
| Mamu-B Molecules | |||||
| SIVmac251 | Env503-511 | EITPIGLAP3 | Mamu-B*01 | U42837 | [19] |
| SIVmac239 | Nef136-146 | ARRHRILDMYL | Mamu-B*03 | U41825 | [9--11] |
| SIVmac239 | Env575-583 | KRQQELLRL | Mamu-B*03 | U41825 | [9--11] |
| SIVmac239 | Nef62-70 | QGQYMNTP | Mamu-B*04 | U41826 | [9--11] |
| SHIV | Env568-576 | NNLLRAIEA | Mamu-B*12 | [16] | |
| SIVmac239 | Nef165-173 | IRYPKTFGW | Mamu-B*17 | [9--11] |
1MHC class I allele designations: Rhesus macaque (Macaca mulatta; Mamu) cynomolgus macaque (Macaca fascicularis; Mafa)
2This CTL epitope, with amino acid substitutions at positions 6 and 7, has been identified in both SIVmac239 and SIVsmE660 infected macaques.
3Note: We have been unable to detect responses to this CTL epitope in Mamu-B*01-defined, SIV-infected rhesus macaques (Allen, unpublished observations)
Table II.CTL Epitopes without Defined Restricting MHC class I Molecules
| Virus | Protein | Epitope | Restriction MHC class I Allele1 | Reference |
| SIVmac251 | Gag35-59 | VWAANELDRFGLAESLLENKEGCQK | unknown | [20] |
| SIVmac251 | Gag35-59 | VWAANELDRFGLAESLLENKEGCQK | unknown | [20] |
| SIVmac251 | Gag246-281 | QIQWMYRQQNPIPVGNIYRRWIQLGLQKCVRMYNPT | unknown | [21--24] |
| SIVmac251 | Gag296-315 | SYVDRFYKSLRAEQTDAAYK | unknown | [25] |
| SIVmac251 | Env21-30 | YCTLYVTVFY | unknown | Allen, unpub |
| SIVmac239 | Env113-121 | CNKSETDRW | unknown | [26] |
| SIVmac251 | Env264-283 | SCTRMMETQTSTWFGFNGTR | unknown | Allen, unpub |
| SIVmac251 | Env294-303 | GRDNRTIISL | unknown | Allen, unpub |
| SIVmac251 | Env314-333 | RRPGNKTVLPVTIMSGLVFH | unknown | Allen, unpub |
| SIVmac251 | Nef108-123 | LRAMTYKLAIDMSHFI | unknown | [21--24] |
| SIVmac251 | Nef128-137 | GLEGIYYSAR | unknown | [21--24] |
| SIVmac251 | Nef164-178 | GIRYPKTFGWLWKLV1 | unknown | [10, 21--24] |
| SIVmac251 | Nef171-179 | FGWLWKLVP | unknown | [9] |
| SIVmac251 | Nef201-225 | SKWDDPWGEVLAWKFDPTLAYTYEA | unknown | [21--24] |
1Responses to the Mamu-B*17-restricted Nef165-173 CTL epitope (last line of Table I, and here underlined) may not completely account for responses to this 15mer.
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
References
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