Clinical control of HIV-1 by cytotoxic T cells specific for multiple conserved epitopes

Journal of Virology

Volumn 89, Issue 10, 2015, Pages 5330-5339

  Murakoshi, Hayato ^a   Akahoshi, Tomohiro ^a   Koyanagi, Madoka ^a   Chikata, Takayuki ^a   Naruto, Takuya ^a   Maruyama, Rie ^a   Tamura, Yoshiko ^a   Ishizuka, Naoki ^b   Gatanaga, Hiroyuki ^a,c   Oka, Shinichi ^a,c   Takiguchi, Masafumi ^a  

^a KUMAMOTO UNIVERSITY   (Japan)

^b CANCER INSTITUTE HOSPITAL   (Japan)

^c NATIONAL CENTER FOR GLOBAL HEALTH AND MEDICINE   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

EPITOPE; HLA B27 ANTIGEN; HLA B57 ANTIGEN; GAG PROTEIN; HLA B ANTIGEN; HLA-B57 ANTIGEN; HUMAN IMMUNODEFICIENCY VIRUS ANTIGEN; HUMAN IMMUNODEFICIENCY VIRUS VACCINE; NEF PROTEIN; NEF PROTEIN, HUMAN IMMUNODEFICIENCY VIRUS 1; POL PROTEIN;

AMINO ACID SEQUENCE; ANTIGEN EXPRESSION; ARTICLE; CD4 LYMPHOCYTE COUNT; CD8+ T LYMPHOCYTE; CROSS REACTION; CYTOTOXIC T LYMPHOCYTE; DISEASE ASSOCIATION; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 SUBTYPE B; IN VIVO STUDY; JAPANESE (PEOPLE); MAJOR CLINICAL STUDY; MOLECULAR RECOGNITION; NONHUMAN; PRIORITY JOURNAL; VIRUS LOAD; ASIAN CONTINENTAL ANCESTRY GROUP; GENETICS; HOST PATHOGEN INTERACTION; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOLOGY; NUCLEOTIDE SEQUENCE; SITE DIRECTED MUTAGENESIS; VIROLOGY;

HUMAN IMMUNODEFICIENCY VIRUS 1;

AIDS VACCINES; ASIAN CONTINENTAL ANCESTRY GROUP; CD4 LYMPHOCYTE COUNT; CONSERVED SEQUENCE; CROSS REACTIONS; EPITOPES, T-LYMPHOCYTE; GAG GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS; HIV ANTIGENS; HIV INFECTIONS; HIV-1; HLA-B ANTIGENS; HLA-B27 ANTIGEN; HOST-PATHOGEN INTERACTIONS; HUMANS; MUTAGENESIS, SITE-DIRECTED; NEF GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS; POL GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS; T-LYMPHOCYTES, CYTOTOXIC; VIRAL LOAD;

EID: 84928524693     PISSN: 0022538X     EISSN: 10985514     Source Type: Journal    
DOI: 10.1128/JVI.00020-15     Document Type: Article

References (46)

1. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH. 2009. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 361: 2209-2220. http://dx.doi.org/10.1056/NEJMoa0908492.
2. Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, Evans DT, Montefiori DC, Karnasuta C, Sutthent R, Liao HX, DeVico AL, Lewis GK, Williams C, Pinter A, Fong Y, Janes H, DeCamp A, Huang Y, Rao M, Billings E, Karasavvas N, Robb ML, Ngauy V, de Souza MS, Paris R, Ferrari G, Bailer RT, Soderberg KA, Andrews C, Berman PW, Frahm N, De Rosa SC, Alpert MD, Yates NL, Shen X, Koup RA, Pitisuttithum P, Kaewkungwal J, Nitayaphan S, Rerks-Ngarm S, Michael NL, Kim JH. 2012. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med 366:1275-1286. http://dx.doi.org/10.1056/NEJMoa1113425.
3. Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, Koblin BA, Buchbinder SP, Keefer MC, Tomaras GD, Frahm N, Hural J, Anude C, Graham BS, Enama ME, Adams E, DeJesus E, Novak RM, Frank I, Bentley C, Ramirez S, Fu R, Koup RA, Mascola JR, Nabel GJ, Montefiori DC, Kublin J, McElrath MJ, Corey L, Gilbert PB. 2013. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N Engl J Med 369:2083-2092. http://dx.doi.org/10.1056/NEJMoa1310566.
4. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, Lederman MM, Benito JM, Goepfert PA, Connors M, Roederer M, Koup RA. 2006. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107:4781-4789. http://dx.doi.org/10.1182/blood-2005-12-4818.
5. Almeida JR, Sauce D, Price DA, Papagno L, Shin SY, Moris A, Larsen M, Pancino G, Douek DC, Autran B, Saez-Cirion A, Appay V. 2009. Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity. Blood 113:6351-6360. http://dx.doi.org/10.1182/blood-2009-02-206557.
6. Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, Hallahan CW, Van Baarle D, Kostense S, Miedema F, McLaughlin M, Ehler L, Metcalf J, Liu S, Connors M. 2002. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 3:1061-1068. http://dx.doi.org/10.1038/ni845.
7. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350-354. http://dx.doi.org/10.1038/nature05115.
8. Iglesias MC, Almeida JR, Fastenackels S, van Bockel DJ, Hashimoto M, Venturi V, Gostick E, Urrutia A, Wooldridge L, Clement M, Gras S, Wilmann PG, Autran B, Moris A, Rossjohn J, Davenport MP, Takiguchi M, Brander C, Douek DC, Kelleher AD, Price DA, Appay V. 2011. Escape from highly effective publicCD8+T-cell clonotypes by HIV. Blood 118:2138-2149. http://dx.doi.org/10.1182/blood-2011-01-328781.
9. Ladell K, Hashimoto M, Iglesias MC, Wilmann PG, McLaren JE, Gras S, Chikata T, Kuse N, Fastenackels S, Gostick E, Bridgeman JS, Venturi V, Arkoub ZA, Agut H, van Bockel DJ, Almeida JR, Douek DC, Meyer L, Venet A, Takiguchi M, Rossjohn J, Price DA, Appay V. 2013. A molecular basis for the control of preimmune escape variants by HIVspecific CD8+ T cells. Immunity 38:425-436. http://dx.doi.org/10.1016/j.immuni.2012.11.021.
10. Sáez-Cirión A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, Boufassa F, Barre-Sinoussi F, Delfraissy JF, Sinet M, Pancino G, Venet A. 2007. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci USA 104:6776-6781. http://dx.doi.org/10.1073/pnas.0611244104.
11. Yang H, Wu H, Hancock G, Clutton G, Sande N, Xu X, Yan H, Huang X, Angus B, Kuldanek K, Fidler S, Denny TN, Birks J, McMichael A, Dorrell L. 2012. Antiviral inhibitory capacity of CD8+T cells predicts the rate of CD4+T-cell decline in HIV-1 infection. J Infect Dis 206:552-561. http://dx.doi.org/10.1093/infdis/jis379.
12. Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, Moodley E, Reddy S, de Pierres C, Mncube Z, Mkhwanazi N, Bishop K, van der Stok M, Nair K, Khan N, Crawford H, Payne R, Leslie A, Prado J, Prendergast A, Frater J, McCarthy N, Brander C, Learn GH, Nickle D, Rousseau C, Coovadia H, Mullins JI, Heckerman D, Walker BD, Goulder P. 2007. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 13:46-53. http://dx.doi.org/10.1038/nm1520.
13. Goulder PJ, Phillips RE, Colbert RA, McAdam S, Ogg G, Nowak MA, Giangrande P, Luzzi G, Morgan B, Edwards A, McMichael AJ, Rowland-Jones S. 1997. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med 3:212-217. http://dx.doi.org/10.1038/nm0297-212.
14. Almeida JR, Price DA, Papagno L, Arkoub ZA, Sauce D, Bornstein E, Asher TE, Samri A, Schnuriger A, Theodorou I, Costagliola D, Rouzioux C, Agut H, Marcelin AG, Douek D, Autran B, Appay V. 2007. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J Exp Med 204:2473-2485. http://dx.doi.org/10.1084/jem.20070784.
15. Leslie AJ, Pfafferott KJ, Chetty P, Draenert R, Addo MM, Feeney M, Tang Y, Holmes EC, Allen T, Prado JG, Altfeld M, Brander C, Dixon C, Ramduth D, Jeena P, Thomas SA, St John A, Roach TA, Kupfer B, Luzzi G, Edwards A, Taylor G, Lyall H, Tudor-Williams G, Novelli V, Martinez-Picado J, Kiepiela P, Walker BD, Goulder PJ. 2004. HIV evolution: CTL escape mutation and reversion after transmission. Nat Med 10:282-289. http://dx.doi.org/10.1038/nm992.
16. Crawford H, Lumm W, Leslie A, Schaefer M, Boeras D, Prado JG, Tang J, Farmer P, Ndung'u T, Lakhi S, Gilmour J, Goepfert P, Walker BD, Kaslow R, Mulenga J, Allen S, Goulder PJ, Hunter E. 2009. Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703-positive individuals and their transmission recipients. J Exp Med 206:909-921.
17. Brockman MA, Schneidewind A, Lahaie M, Schmidt A, Miura T, Desouza I, Ryvkin F, Derdeyn CA, Allen S, Hunter E, Mulenga J, Goepfert PA, Walker BD, Allen TM. 2007. Escape and compensation from early HLA-B57-mediated cytotoxic T-lymphocyte pressure on human immunodeficiency virus type 1 Gag alter capsid interactions with cyclophilin A. J Virol 81:12608-12618. http://dx.doi.org/10.1128/JVI.01369-07.
18. Watanabe K, Murakoshi H, Tamura Y, Koyanagi M, Chikata T, Gatanaga H, Oka S, Takiguchi M. 2013. Identification of cross-clade CTL epitopes in HIV-1 clade A/E-infected individuals by using the clade B overlapping peptides. Microbes Infect 15:874-886. http://dx.doi.org/10.1016/j.micinf.2013.08.002.
19. Yagita Y, Kuse N, Kuroki K, Gatanaga H, Carlson JM, Chikata T, Brumme ZL, Murakoshi H, Akahoshi T, Pfeifer N, Mallal S, John M, Ose T, Matsubara H, Kanda R, Fukunaga Y, Honda K, Kawashima Y, Ariumi Y, Oka S, Maenaka K, Takiguchi M. 2013. Distinct HIV-1 escape patterns selected by cytotoxic T cells with identical epitope specificity. J Virol 87:2253-2263. http://dx.doi.org/10.1128/JVI.02572-12.
20. Watanabe T, Murakoshi H, Gatanaga H, Koyanagi M, Oka S, Takiguchi M. 2011. Effective recognition of HIV-1-infected cells by HIV-1 integrasespecific HLA-B *4002-restricted T cells. Microbes Infect 13:160-166. http://dx.doi.org/10.1016/j.micinf.2010.10.006.
21. Fujiwara M, Tanuma J, Koizumi H, Kawashima Y, Honda K, Mastuoka-Aizawa S, Dohki S, Oka S, Takiguchi M. 2008. Different abilities of escape mutant-specific cytotoxic T cells to suppress replication of escape mutant and wild-type human immunodeficiency virus type 1 in new hosts. J Virol 82:138-147. http://dx.doi.org/10.1128/JVI.01452-07.
22. Borghan MA, Oka S, Takiguchi M. 2005. Identification of HLA-A*3101-restricted cytotoxic T-lymphocyte response to human immunodeficiency virus type 1 (HIV-1) in patients with chronic HIV-1 infection. Tissue Antigens 66:305-313. http://dx.doi.org/10.1111/j.1399-0039.2005.00489.x.
23. Honda K, Zheng N, Murakoshi H, Hashimoto M, Sakai K, Borghan MA, Chikata T, Koyanagi M, Tamura Y, Gatanaga H, Oka S, Takiguchi M. 2011. Selection of escape mutant by HLA-C-restricted HIV-1 Pol-specific cytotoxic T lymphocytes carrying strong ability to suppress HIV-1 replication. Eur J Immunol 41:97-106. http://dx.doi.org/10.1002/eji.201040841.
24. Koizumi H, Hashimoto M, Fujiwara M, Murakoshi H, Chikata T, Borghan MA, Hachiya A, Kawashima Y, Takata H, Ueno T, Oka S, Takiguchi M. 2010. Different in vivo effects of HIV-1 immunodominant epitope-specific cytotoxic T lymphocytes on selection of escape mutant viruses. J Virol 84:5508-5519. http://dx.doi.org/10.1128/JVI.02483-09.
25. Falk K, Rotzschke O, Takiguchi M, Gnau V, Stevanovic S, Jung G, Rammensee HG. 1995. Peptide motifs of HLA-B58, B60, B61, and B62 molecules. Immunogenetics 41:165-168. http://dx.doi.org/10.1007/BF00182333.
26. Naruto T, Gatanaga H, Nelson G, Sakai K, Carrington M, Oka S, Takiguchi M. 2012. HLA class I-mediated control of HIV-1 in the Japanese population, in which the protective HLA-B*57 and HLAB* 27 alleles are absent. J Virol 86:10870-10872. http://dx.doi.org/10.1128/JVI.00689-12.
27. Chikata T, Carlson JM, Tamura Y, Borghan MA, Naruto T, Hashimoto M, Murakoshi H, Le AQ, Mallal S, John M, Gatanaga H, Oka S, Brumme ZL, Takiguchi M. 2014. Host-specific adaptation of HIV-1 subtype B in the Japanese population. J Virol 88:4764-4775. http://dx.doi.org/10.1128/JVI.00147-14.
28. Edwards BH, Bansal A, Sabbaj S, Bakari J, Mulligan MJ, Goepfert PA. 2002. Magnitude of functionalCD8+T-cell responses to the gag protein of human immunodeficiency virus type 1 correlates inversely with viral load in plasma. J Virol 76:2298-2305. http://dx.doi.org/10.1128/jvi.76.5.2298-2305.2002.
29. Zuñiga R, Lucchetti A, Galvan P, Sanchez S, Sanchez C, Hernandez A, Sanchez H, Frahm N, Linde CH, Hewitt HS, Hildebrand W, Altfeld M, Allen TM, Walker BD, Korber BT, Leitner T, Sanchez J, Brander C. 2006. Relative dominance of Gag p24-specific cytotoxic T lymphocytes is associated with human immunodeficiency virus control. J Virol 80:3122-3125. http://dx.doi.org/10.1128/JVI.80.6.3122-3125.2006.
30. Addo MM, Yu XG, Rathod A, Cohen D, Eldridge RL, Strick D, Johnston MN, Corcoran C, Wurcel AG, Fitzpatrick CA, Feeney ME, Rodriguez WR, Basgoz N, Draenert R, Stone DR, Brander C, Goulder PJ, Rosenberg ES, Altfeld M, Walker BD. 2003. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J Virol 77:2081-2092. http://dx.doi.org/10.1128/JVI.77.3.2081-2092.2003.
31. Frahm N, Korber BT, Adams CM, Szinger JJ, Draenert R, Addo MM, Feeney ME, Yusim K, Sango K, Brown NV, Sen Gupta D, Piechocka-Trocha A, Simonis T, Marincola FM, Wurcel AG, Stone DR, Russell CJ, Adolf P, Cohen D, Roach T, St John A, Khatri A, Davis K, Mullins J, Goulder PJ, Walker BD, Brander C. 2004. Consistent cytotoxic-Tlymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities. J Virol 78:2187-2200. http://dx.doi.org/10.1128/JVI.78.5.2187-2200.2004.
32. Jia M, Hong K, Chen J, Ruan Y, Wang Z, Su B, Ren G, Zhang X, Liu Z, Zhao Q, Li D, Peng H, Altfeld M, Walker BD, Yu XG, Shao Y. 2012. Preferential CTL targeting of Gag is associated with relative viral control in long-term surviving HIV-1 infected former plasma donors from China. Cell Res 22:903-914. http://dx.doi.org/10.1038/cr.2012.19.
33. Borthwick N, Ahmed T, Ondondo B, Hayes P, Rose A, Ebrahimsa U, Hayton EJ, Black A, Bridgeman A, Rosario M, Hill AV, Berrie E, Moyle S, Frahm N, Cox J, Colloca S, Nicosia A, Gilmour J, McMichael AJ, Dorrell L, Hanke T. 2014. Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. Mol Ther 22:464-475. http://dx.doi.org/10.1038/mt.2013.248.
34. Novitsky V, Gilbert P, Peter T, McLane MF, Gaolekwe S, Rybak N, Thior I, Ndung'u T, Marlink R, Lee TH, Essex M. 2003. Association between virus-specific T-cell responses and plasma viral load in human immunodeficiency virus type 1 subtype C infection. J Virol 77:882-890. http://dx.doi.org/10.1128/JVI.77.2.882-890.2003.
35. Masemola A, Mashishi T, Khoury G, Mohube P, Mokgotho P, Vardas E, Colvin M, Zijenah L, Katzenstein D, Musonda R, Allen S, Kumwenda N, Taha T, Gray G, McIntyre J, Karim SA, Sheppard HW, Gray CM. 2004. Hierarchical targeting of subtype C human immunodeficiency virus type 1 proteins by CD8+ T cells: correlation with viral load. J Virol 78: 3233-3243. http://dx.doi.org/10.1128/JVI.78.7.3233-3243.2004.
36. Geldmacher C, Currier JR, Herrmann E, Haule A, Kuta E, McCutchan F, Njovu L, Geis S, Hoffmann O, Maboko L, Williamson C, Birx D, Meyerhans A, Cox J, Hoelscher M. 2007. CD8 T-cell recognition of multiple epitopes within specific Gag regions is associated with maintenance of a low steady-state viremia in human immunodeficiency virus type 1-seropositive patients. J Virol 81:2440-2448. http://dx.doi.org/10.1128/JVI.01847-06.
37. Mothe B, Llano A, Ibarrondo J, Daniels M, Miranda C, Zamarreno J, Bach V, Zuniga R, Perez-Alvarez S, Berger CT, Puertas MC, Martinez-Picado J, Rolland M, Farfan M, Szinger JJ, Hildebrand WH, Yang OO, Sanchez-Merino V, Brumme CJ, Brumme ZL, Heckerman D, Allen TM, Mullins JI, Gomez G, Goulder PJ, Walker BD, Gatell JM, Clotet B, Korber BT, Sanchez J, Brander C. 2011. Definition of the viral targets of protective HIV-1-specific T cell responses. J Transl Med 9:208. http://dx.doi.org/10.1186/1479-5876-9-208.
38. Streeck H, Lu R, Beckwith N, Milazzo M, Liu M, Routy JP, Little S, Jessen H, Kelleher AD, Hecht F, Sekaly RP, Alter G, Heckerman D, Carrington M, Rosenberg ES, Altfeld M. 2014. Emergence of individual HIV-specific CD8 T cell responses during primary HIV-1 infection can determine long-term disease outcome. J Virol 88:12793-12801. http://dx.doi.org/10.1128/JVI.02016-14.
39. Pereyra F, Heckerman D, Carlson JM, Kadie C, Soghoian DZ, Karel D, Goldenthal A, Davis OB, DeZiel CE, Lin T, Peng J, Piechocka A, Carrington M, Walker BD. 2014. HIV control is mediated in part by CD8+ T-cell targeting of specific epitopes. J Virol 88:12937-12948. http://dx.doi.org/10.1128/JVI.01004-14.
40. Létourneau S, Im EJ, Mashishi T, Brereton C, Bridgeman A, Yang H, Dorrell L, Dong T, Korber B, McMichael AJ, Hanke T. 2007. Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One 2:e984. http://dx.doi.org/10.1371/journal.pone.0000984.
41. Rolland M, Nickle DC, Mullins JI. 2007. HIV-1 group M conserved elements vaccine. PLoS Pathog 3:e157. http://dx.doi.org/10.1371/journal.ppat.0030157.
42. Rowland-Jones SL, Dong T, Fowke KR, Kimani J, Krausa P, Newell H, Blanchard T, Ariyoshi K, Oyugi J, Ngugi E, Bwayo J, MacDonald KS, McMichael AJ, Plummer FA. 1998. Cytotoxic T cell responses to multiple conserved HIV epitopes in HIV-resistant prostitutes in Nairobi. J Clin Invest 102:1758-1765. http://dx.doi.org/10.1172/JCI4314.
43. Knudsen ML, Mbewe-Mvula A, Rosario M, Johansson DX, Kakoulidou M, Bridgeman A, Reyes-Sandoval A, Nicosia A, Ljungberg K, Hanke T, Liljestrom P. 2012. Superior induction of T cell responses to conserved HIV-1 regions by electroporated alphavirus replicon DNA compared to that with conventional plasmid DNA vaccine. J Virol 86:4082-4090. http://dx.doi.org/10.1128/JVI.06535-11.
44. Rosario M, Borthwick N, Stewart-Jones GB, Mbewe-Mvula A, Bridgeman A, Colloca S, Montefiori D, McMichael AJ, Nicosia A, Quakkelaar ED, Drijfhout JW, Melief CJ, Hanke T. 2012. Prime-boost regimens with adjuvanted synthetic long peptides elicit T cells and antibodies to conserved regions of HIV-1 in macaques. AIDS 26:275-284. http://dx.doi.org/10.1097/QAD.0b013e32834ed9b2.
45. Rosario M, Bridgeman A, Quakkelaar ED, Quigley MF, Hill BJ, Knudsen ML, Ammendola V, Ljungberg K, Borthwick N, Im EJ, McMichael AJ, Drijfhout JW, Greenaway HY, Venturi V, Douek DC, Colloca S, Liljestrom P, Nicosia A, Price DA, Melief CJ, Hanke T. 2010. Long peptides induce polyfunctional T cells against conserved regions of HIV-1 with superior breadth to single-gene vaccines in macaques. Eur J Immunol 40:1973-1984. http://dx.doi.org/10.1002/eji.201040344.
46. Storey JD, Tibshirani R. 2003. Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100:9440-9445. http://dx.doi.org/10.1073/pnas.1530509100.