Supplemental Table 1. CD8 + and CD4 + T cell epitopes identified in EBV lytic and latent cycle proteins. CD8 + T cell epitopes.

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1 Supplemental Table 1. CD8 + and CD4 + T cell epitopes identified in EBV lytic and latent cycle proteins. CD8 + T cell epitopes EBV Antigen Epitope Coordinates Epitope Sequence HLA Restriction References Latent Cycle Proteins EBNA RPQKRPSCI B7 (S1) HPVGEADYF B53 (S1) HPVGEADYFEY B35.01 (S2) IPQCRLTPL B7 (S1) VLKDAIKDL A2.03 (S2) EBNA YHLIVDTDSL B38 (S3) DTPLIPLTIF A2/B51 (S4) RPTELQPTP B55 (S5) EBNA3A QAKWRLQTL B8 (S6) AYSSWMYSY A30.02 (S7) RYSIFFDY A24 (S6) FLRGRAYGL B8 (S8) KRPPIFIRRL B27 (S9) RPPIFIRRL B7 (S10) LEKARGSTY B62 (S11) HLAAQGMAY (S6) YPLHEQHGM B35.01 (S6) VFSDGRVAC A29 (S11) VPAPAGPIV B7 (S11) SVRDRLARL A2 (S6) RLRAEAQVK A3 (S12) VQPPQLTLQV B46 (S13) EBNA3B HRCQAIRKK B27.05 (S11) TYSAGIVQI A24.02 (S11) RRARSLSAERY B27.02 (S14) VSFIEFVGW B58 (S15) AVFDRKSDAK A11 (S16) IVTDFSVIK A11 (S16) AVLLHEESM B35.01 (S11) VEITPYKPTW B44 (S11) EBNA3C EGGVGWRHW B44.03 (S17) QNGALAINTF B62 (S18) LRGKWQRRYR B27.05 (S14) RRIYDLIEL B27.02/.04/.05 (S14) HHIWQNLL B39 (S11) EENLLDFVRF B44.02 (S19) LLDFVRFMGV A2.01 (S18) LDFVRFMGV B37 (S20) KEHVIQNAF B44.02 (S21) FRKAQIQGL B27.05 (S14) QPRAPIRPI B7 (S10)

2 EBNA-LP SLREWLLRI A2 (S15) LMP FWLYIVMSD (S22) FRRDLLCPLGA B40 (S22) YLLEMLWRL A2 (S23) YLQQNWWTL A2 (S23) TLLVDLLWL A2 (S23) DPHGPVQLSYYD B51.1 (S22) LMP2 1-9 MGSLEMVPM B35.01 (S24) EDPYWGNGDRHSDYQ (S22) NPVCLPVIVAPYLF (S22) LPVIVAPYL B53 (S24) PYLFWLAAI A23 (S25) ASCFTASVSTVVTA (S22) FTASVSTVV A68 (S24) IEDPPFNSL B40.01 (S26) RRRWRRLTV B27.04 (S14) RRWRRLTVC B14.02 (S24) RRLTVCGGIMF B27 (S24) TVCGGIMFL A1 (S24) MFLACVLVLIVDAV (S22) LIVDAVLQL A2 (S24) GLGTLGAAI A2 (S22) LLWTLVVLL A2.01 (S26) SSCSSCPLSKI A11 (S26) ILLARLFLY A29 (S24) FLYALALLL A2 (S27) TYGPVFMCL A24 (S26) CLGGLLTMV A2.01 (S28) VMSNTLLSAW A25 (S11) LTAGFLIFL A2.06 (S26) LLSAWILTA A2 (S15) Lytic Cycle Proteins BRLF LVSDYCNVLNKEFT B18 (S29) LVSDYCNVL A2.05 (S30) DYCNVLNKEF A24 (S29) AENAGNDAC B45 (S31) IACPIVMRYYVLDHLI A24/C2 (S31) YVLDHLIVV A2.01 (S32) FFIQAPSNRVMIPAT (S29) ATIGTAMYK A11 (S29) KHSRVRAYTYSKVLG A3 (S29) RALIKTLPRASYSSH A2 (S29) ERPIFPHPSKPTFLP Cw4 (S29) QKEEAAICGQMDLS B61 (S29) EVCQPKRIRPFHPPG (S29) BZLF LPEPLPQGQLTAY B35.08 (S33) EPLPQGQLTAY B35.01 (S32) APENAYQAY B35.01 (S34) LQHYREVAA C8 (S31) DSELEIKRYKNR B18 (S32) RKCCRAKFKQLLQHYR C6 (S35) RAKFKQLL B8 (S35) SENDRLRLL B60 (S36)

3 BMLF KDTWLDARM (S37) GLCTLVAML A2.01 (S36, S37) DEVEFLGHY B18 (S37) SRLVRAILSP B14 (S30) BMRF CYDHAQTHL A2 (S31) FRNLAYGRTCVLGKE C3/C10 (S37) RPQGGSRPEFVKL B7 (S31) TLDYKPLSV A2.01 (S38) YRSGIIAVV C6 (S37) YRSGIIAVV B39 (S31) LPLDLSVILF B53 (S30) BARF0 LLWAARPRL A2 (S39) BCRF RRLVVTLQC B27 (S40) BALF ARYAYYLQF B27 (S31) BILF RRRKGWIPL B27 (S31) BLLF1 VLQWASLAV A2 (S41) (gp350) BALF FLDKGTYTL A2 (S31) (gp110) ILIYNGWYA A2 (S42) VPGSETMCY B35 (S42) APGWLIWTY B35 (S42) BXLF2 TLFIGSHVV A2.01 (S41) (gp85) SLVIVTTFV A2.01 (S41) LMIIPLINV A2.01 (S41)

4 CD4 + T cell epitopes EBV Antigen Epitope Coordinates Epitope Sequence HLA Restriction References Latent Cycle Proteins EBNA RRPQKRPSCIGCKGT (S43) RPFFHPVGEADYFEY (S43) VPPGAIEQGPADDPGEGPST (S43) IEQGPTDDPGEGPSTGPRGQGDGGR (S44) DGGRRKKGGWFGRHR (S43) SNPKFENIAEGLRVLLARSH (S44) NPKFENIAEGLRALL (S43) ENIAEGLRVLLARSHVERTT DQ7 (S44) IAEGLRALLARSHVERTTDE DQ2/3 (S45) LRALLARSHVERTTD (S43) EEGNWVAGVFVYGGSKTSLYNLRRG (S44) VYGGSKTSLYNLRRGTALAI DR11 (S43) TSLYNLRRGTALAI DR1 (S46) YNLRRGTALAIPQ DP3 (S47) NLRRGRTALAIPQCRL (S43) EEGNWVAGVFVYGGSKTSLYNLRRG (S44) AIPQCRLTPLSRLPF DR13 (S48) PQCRLTPLSRLPFGM DR14 (S43) APGPGPQPLRESIVCYFM (S43) PQPGPLRESIVCYFMVFLQT (S44) PGPLRESIVCYFMVFLQTHI DR1 (S45) LRESIVCYFMVFLQTHIFAE (S43) LRESIVCYFMVFLQTHIFAEVLKDA (S44) YFMVFLQTHIFAE DR11,12,13 (S49) MVFLQTHIFAEVLKD DR15 (S43) VFLQTHIFAEVLKDAIKDL DP5 (S44) VLKDAIKDLVMTKPAPTCNI (S43) PTCNIKVTVCSFDDGVDLPPWFPPM (S44) RVTVCSFDDGVDLPPWFPPM (S43) PPWFPPMVEGAAA DQ2 (S49) EBNA GQTYHLIVDTLALHGGQTYH DR4 (S50) IPLTIFVGENTGVPPPLPPP (S50) MRMLWMANYIVRQSRGDRGL (S50) LPPATLVPPRPTRPTTLPP (S50) PRSTVFYNIPPMPLPPSQL DR7,52a,52b,52c (S50) TVFYNIPPMPL DQ2/DQ7 (S51) PAQPPPGVINDQQLHHLPSG DR17 (S50) EBNA3A EDLPCIVSRGGPKVKRPPIF DR15 (S50) GPWVPEQWMFQGAPPSQGTP DR1 (S50) QVADVVRAPGVPAMQPQYF (S50) EBNA3B EBNA3C NRGWMQRIRRRRRR (S43)

5 PHDITYPYTARNIRDAACRAV DR16 (S52) ILCFVMAARQRLQDI DR13 (S43) SDDELPYIDPNMEPV DQ5 (S43) QQRPVMFVSRVPAKK (S43) QKRAAPPTVSPSDTG (S43) PPAAGPPAAGPRILA (S43) PPVVRMFMRERQLPQ (S43) PQCFWEMRAGREITQ (S43) PAPQAPYQGYQEPPAPQAPY DR1/DR4 (S53) PSMPFASDYSQGAFT (S43) AQEILSDNSEISVFPK (S43) LMP GPPRPPLGPPLSSSIGLALL DR7 & DR9 (S54) LWRLGATIWQLLAFF (S43) LIWMYYHGPRHTDEHHHDDS DR16 (S54) QATDDSSHESDSNSNEGRHH DQ2 (S54) SSHESDSNSNEGRHHLLVSG DQB1*0601 (S54) SGHESDSNSNEGRHHH (S43) TDGGGGHSHDSGHGG (S43) LMP DYQPLGTQDQSLYLG DR4 or DR16 (S24) STVVTATGLALSLLL (S43) SSYAAAQRKLLTPV (S43) VTFFAICLTWRIEDPPFNSI DRB1*0901 (S54) ICLTWRIEDPPFNSILFALL DRB1*1001 (S54) VLVMLVLLILAYRRRWRRLT (S43) STEFIPNLFCMLLL (S43) TYGPVFMSLGGLLTMVAGAV DQB1*0601 (S54) Lytic Cycle Proteins BHRF AGLTLSLLVICSYLFISRG DR2 (S55) PYYVVDLSVRGM DR4 (S52) TVVLRYHVLLEEI DR4 (S56) BZLF ELEIKRYKNRVASRK DR13 (S57) KSSENDRLRLLLKQM DQB1*0402 (S57) BLLF LDLFGQLTPHTKAVYQPRGA DRw15 (S58) (gp350) FGQLTPHTKAVYQPR DRB1*1301 (S57) VYFQDVFGTMWCHHA DQB1*0402 (S57) DNCNSTNI TAVVRAQGLDVTL DRw11 (S58) BALF AWCLEQKRQNMVLRE DPB1*1301 (S57) (gp110) DNEIFLTKKMTEVCQ DRB1*0801 (S57) Note: Epitopes in italics have been identified in Chinese donors, the epitope sequences displayed for these epitopes are from a reference type 1 Chinese EBV isolate (S59).

6 S1. Blake N, Haigh T, Shaka'a G, Croom-Carter D, Rickinson A The importance of exogenous antigen in priming the human CD8 + T cell response: Lessons from the EBV nuclear antigen EBNA1. J. Immunol. 165: S2. Blake N, Lee SP, Redchenko I, Thomas WA, Steven N, et al Human CD8 + T cell responses to EBV EBNA1: HLA class I presentation of the (Gly-Ala)-containing protein requires exogenous processing. Immunity 7: S3. Chapman AL, Rickinson AB, Thomas WA, Jarrett RF, Crocker J, et al Epstein-Barr virusspecific cytotoxic T lymphocyte responses in the blood and tumour site of Hodgkin's disease patients: Implications for a T cell-based therapy. Cancer Res. 61: S4. Schmidt C, Burrows SR, Sculley TB, Moss DJ, Misko IS Non-responsiveness to an immunodominant Epstein-Barr virus- encoded cytotoxic T-lymphocyte epitope in nuclear antigen 3A: Implications for vaccine strategies. Proc. Natl. Acad. Sci. USA 88: S5. Mackay LK. unpublished data. S6. Burrows SR, Gardner J, Khanna R, Steward T, Moss DJ, et al Five new cytotoxic T-cell epitopes identified within Epstein-Barr virus nuclear antigen 3. J. Gen. Virol. 75: S7. Steven NM, Leese AM, Annels N, Lee S, Rickinson AB Epitope focusing in the primary cytotoxic T-cell response to Epstein-Barr virus and its relationship to T-cell memory. J. Exp. Med. 184: S8. Burrows SR, Sculley TB, Misko IS, Schmidt C, Moss DJ An Epstein-Barr virus-specific cytotoxic T cell epitope in EBNA3. J. Exp. Med. 171: S9. Brooks J. unpublished data. S10. Hill AB, Worth A, Elliott T, Rowland-Jones S, Brooks JM, et al Characterisation of two Epstein-Barr virus epitopes restricted by HLA-B7. Eur. J. Immunol. 25:18-24 S11. Rickinson AB, Moss DJ Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection. Ann. Rev. Immunol. 15: S12. Hill AB, Lee SP, Haurum JS, Murray N, Yao QY, et al Class I major histocompatibility complex-restricted cytotoxic T lymphocytes specific for Epstein-Barr virus (EBV) nuclear antigens fail to lyse the EBV-transformed B lymphoblastoid lines against which they were raised. J. Exp. Med. 181: S13. Whitney BM, Chan AT, Rickinson AB, Lee SP, Lin CK, et al Frequency of Epstein-Barr virus-specific cytotoxic T lymphocytes in the blood of Southern Chinese blood donors and nasopharyngeal carcinoma patients. J. Med. Virol. 67: S14. Brooks JM, Murray RJ, Thomas WA, Kurilla MG, Rickinson AB Different HLA-B27 subtypes present the same immunodominant Epstein-Barr virus peptide. J. Exp. Med. 178: S15. Lee SP, Chan ATC, Cheung S-T, Thomas WA, Croom-Carter D, et al CTL control of EBV in nasopharyngeal carcinoma (NPC): EBV-specific CTL responses in the blood and tumours of NPC patients and the antigen-processing function of the tumour cells. J. Immunol. 165: S16. Gavioli R, Kurilla MG, de Campos-Lima PO, Wallace LE, Dolcetti R, et al Multiple HLA- A11-restricted cytotoxic T-lymphocyte epitopes of different immunogenicities in the Epstein-Barr virus-encoded nuclear antigen 4. J. Virol. 67: S17. Morgan SM, Wilkinson GWG, Floettmann E, Blake N, Rickinson AB A recombinant adenovirus expressing an Epstein-Barr virus (EBV) target antigen can selectively reactivate rare components of EBV cytotoxic T-lymphocyte memory in vitro. J. Virol. 70: S18. Kerr BM, Kienzle N, Burrows J, Cross S, Silins S, et al Identification of type B specific and crossreactive EBV CTL responses in recovery phase of infectious mononucleosis. J. Virol. 70: S19. Burrows SR, Misko IS, Sculley TB, Schmidt D, Moss DJ An Epstein-Barr virus-specific cytotoxic T cell epitope present on A- and B-type transformants. J. Virol. 64: S20. Shi Y, Smith KD, Kurilla MG, Lutz CT Cytotoxic CD8 + T cells recognize EBV antigen but poorly kill autologous EBV-infected B lymphoblasts: immunodominance is elicited by a peptide epitope that is presented at low levels in vitro. J. Immunol. 159: S21. Khanna R, Burrows SR, Kurilla MG, Jacob CA, Misko IS, et al Localisation of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: Implications for vaccine development. J. Exp. Med. 176:169-78

7 S22. Meij P, Leen A, Rickinson AB, Verkoeijen S, Vervoort MB, et al Identification and prevalence of CD8 + T-cell responses directed against Epstein-Barr virus-encoded latent membrane protein 1 and latent membrane protein 2. Int J Cancer. 99:93-9. S23. Khanna R, Burrows SR, Nicholls J, Poulsen LM Identification of cytotoxic T cell epitopes within Epstein-Barr virus (EBV) oncogene latent membrane protein 1 (LMP1): Evidence for HLA- A2 supertype-restricted immune recognition of EBV-infected cells by LMP1-specific cytotoxic T lymphocytes. Eur. J. Immunol. 28: S24. Straathof KC, Leen AM, Buza EL, Taylor G, Huls MH, et al Characterization of latent membrane protein 2 specificity in CTL lines from patients with EBV-positive nasopharyngeal carcinoma and lymphoma. J. Immunol. 175: S25. Khanna R, Burrows SR, Moss DJ, Silins SL Peptide transporter (TAP-1 and TAP-2)- independent endogenous processing of Epstein-Barr virus (EBV) latent membrane protein 2A: Implications for cytotoxic T-lymphocyte control of EBV-associated malignancies. J. Virol. 70: S26. Lee SP, Thomas WA, Blake NW, Rickinson AB Transporter (TAP)-independent processing of a multiple membrane- spanning protein, the Epstein-Barr virus latent membrane protein 2. Eur. J. Immunol. 26: S27. Lautscham G, Haigh T, Mayrhofer S, Taylor G, Croom-Carter D, et al Identification of a TAP-independent, immunoproteasome-dependent CD8 + T-cell epitope in Epstein-Barr virus latent membrane protein 2. J. Virol. 77: S28. Lee SP, Thomas WA, Murray RJ, Khanim F, Kaur S, et al HLA A2.1-restricted cytotoxic T cells recognizing a range of Epstein-Barr virus isolates through a defined epitope in latent membrane protein LMP2. J. Virol. 67: S29. Pepperl S, Benninger-Doring G, Modrow S, Wolf H, Jilg W Immediate-early transactivator Rta of Epstein-Barr virus (EBV) shows multiple epitopes recognized by EBV-specific cytotoxic T lymphocytes. J. Virol. 72: S30. Annels NE. unpublished data. S31. Pudney VA, Leese AM, Rickinson AB, Hislop AD CD8 + immunodominance among Epstein- Barr virus lytic cycle antigens directly reflects the efficiency of antigen presentation in lytically infected cells. J. Exp. Med. 201: S32. Saulquin X, Ibisch C, Peyrat M-A, Scotet E, Hourmant M, et al A global appraisal of immunodominant CD8 T cell responses to Epstein-Barr virus and cytomegalovirus by bulk screening. Eur. J. Immunol. 30: S33. Green KJ, Miles JJ, Tellam J, van Zuylen WJM, Connelly G, et al Potent T cell response to a class I-binding 13-mer viral epitope and the influence of HLA micropolymorphism in controlling epitope length. Eur J Immunol. 34: S34. Redchenko I, Rickinson AB Accessing Epstein-Barr virus-specific T cell memory with peptide-loaded dendritic cells. J. Virol. 73: S35. Bogedain C, Wolf H, Modrow S, Stuber G, Jilg W Specific cytotoxic T-lymphocytes recognize the immediate-early transactivator ZTA of Epstein-Barr virus. J. Virol. 69: S36. Scotet E, David-Ameline J, Peyrat MA, Moreau-Aubry A, Pinczon D, et al T cell response to Epstein-Barr virus transactivators in chronic rheumatoid arthritis. J. Exp. Med. 184: S37. Steven NM, Annels N, Kumar A, Leese A, Kurilla MG, et al Immediate early and early lytic cycle proteins are frequent targets of the Epstein-Barr virus-induced cytotoxic T cell response. J. Exp. Med. 185: S38. Hislop AD, Annels NE, Gudgeon NH, Leese AM, Rickinson AB Epitope-specific evolution of human CD8 + T cell responses from primary to persistent phases of Epstein-Barr virus infection. J. Exp. Med. 195: S39. Kienzle N, Sculley TB, Poulsen L, Buck M, Cross S, et al Identification of a cytotoxic T- lymphocyte response to the novel BARF0 protein of Epstein-Barr virus:a critical role for antigen expression. J. Virol. 72: S40. Saulquin X, Bodinier M, Peyrat MA, Hislop A, Scotet E, et al Frequent recognition of BCRF1, a late lytic cycle protein of Epstein-Barr virus, in the HLA-B*2705 context: evidence for a TAP-independent processing. Eur. J. Immunol. 31: S41. Khanna R, Sherritt M, Burrows SR EBV structural antigens, gp350 and gp85, as targets for ex vivo virus-specific CTL during acute infectious mononucleosis: Potential use of gp350/gp85 CTL epitopes for vaccine design. J. Immunol. 162: S42. Khanna R, Burrows SR Role of cytotoxic T lymphocytes in Epstein-Barr virus-associated diseases. Annu. Rev. Microbiol. 54:19-48

8 S43. Leen A, Meji P, Redchenko I, Middeldorp JM, Bloemena E, et al Differential immunogenicity of Epstein-Barr virus latent-cycle preoteins for human CD4 + T-helper 1 responses. J. Virol. 75: S44. Tsang CW, Lin X, Gudgeon NH, Taylor GS, Jia H, et al CD4 + T-Cell Responses to Epstein- Barr Virus Nuclear Antigen EBNA1 in Chinese Populations Are Highly Focused on Novel C- Terminal Domain-Derived Epitopes. J. Virol. 80: S45. Paludan C, Bickham K, Nikiforow S, Tsang ML, Goodman K, et al Epstein-Barr Nuclear Antigen 1-Specific CD4 + Th1 Cells Kill Burkitt's Lymphoma Cells. J. Immunol. 169: S46. Khanna R, Burrows SR, Steigerwald-Mullen PM, Thomson SA, Kurilla MG, et al Isolation of cytotoxic T lymphocytes from healthy seropositive individuals specific for peptide epitopes from Epstein-Barr virus nuclear antigen 1: Implications for viral persistence and tumour surveillance. Virology 214: S47. Voo KS, Fu T, Heslop HE, Brenner MK, Rooney CM, et al Identification of HLA-DP3- restricted peptides from EBNA1 recognized by CD4 + T cells. Cancer Res 62: S48. Mautner J, Pich D, Nimmerjahn F, Milosevic S, Adhikary D, et al Epstein-Barr virus nuclear antigen 1 evades direct immune recognition by CD4 + T helper cells. Eur. J. Immunol. 34: S49. Voo KS, Peng G, Guo Z, Fu T, Li Y, et al Functional Characterization of EBV-Encoded Nuclear Antigen 1-Specific CD4 + Helper and Regulatory T Cells Elicited by In vitro Peptide Stimulation. Cancer Res 65: S50. Long HM, Haigh TA, Gudgeon NH, Leen AM, Tsang C-W, et al CD4 + T-Cell Responses to Epstein-Barr Virus (EBV) Latent-Cycle Antigens and the Recognition of EBV-Transformed Lymphoblastoid Cell Lines. J. Virol. 79: S51. Khanna R, Burrows SR, Thomson SA, Moss DJ, Cresswell P, et al Class I processingdefective Burkitt's lymphoma cells are recognised efficiently by CD4 + EBV-specific CTLs. J. Immunol. 158: S52. Landais E, Saulquin X, Scotet E, Trautmann L, Peyrat M-A, et al Direct killing of Epstein- Barr virus (EBV)-infected B cells by CD4 T cells directed against the EBV lytic protein BHRF1. Blood 103: S53. Rajnavolgyi E, Nagy N, Thuresson B, Dosztanyi Z, Simon A, et al A repetitive sequence of Epstein-Barr virus nuclear antigen 6 comprises overlapping T cell epitopes which induce HLA-DRrestricted CD4 + T lymphocytes. Int. Immunol. 12: S54. Haigh TA. unpublished data. S55. White CA, Cross SM, Kurilla MG, Kerr BM, Schmidt C, et al Recruitment during infectious mononucleosis of CD3 + CD4 + CD8 + virus-specific cytotoxic T cells which recognise Epstein-Barr virus lytic antigen BHRF1. Virology 219: S56. Schmidt CW, Misko IS The ecology and pathology of Epstein-Barr virus. Immunol. Cell Biol. 73: S57. Adhikary D, Behrends U, Moosmann A, Witter K, Bornkamm GW, et al Control of Epstein- Barr virus infection in vitro by T helper cells specific for virion glycoproteins. J. Exp. Med. 203: S58. Wallace LE, Wright J, Ulaeto DO, Morgan AJ, Rickinson AB Identification of two T cell epitopes on the candidate Epstein- Barr virus vaccine glycoprotein gp340 recognised by CD4 + T cell clones. J. Virol. 65: S59. Taylor GS, Haigh TA, Gudgeon NH, Phelps RJ, Lee SP, et al Dual Stimulation of Epstein- Barr Virus (EBV)-Specific CD4 + - and CD8 + -T-Cell Responses by a Chimeric Antigen Construct: Potential Therapeutic Vaccine for EBV-Positive Nasopharyngeal Carcinoma. J. Virol. 78:768-78

Number of Patients Susceptibility Reference HLA-A* (278 EBV+) Increased incidence of. [1] EBV + chl 516 (192 EBV+) Increased incidence of

Supporting Information: Table S1. Previously published HLA-class I associations with. Number of Patients Susceptibility Reference HLA-A*01 934 (278 EBV+) Increased incidence of [1] 516 (192 EBV+) Increased