Identification of Effective Subdominant Anti-HIV-1 CD8+ T Cells Within Entire Post-infection and Post-vaccination Immune Responses

English version České info

Attempts to develop an HIV vaccine that elicits potent cell-mediated immunity have so far been unsuccessful. This is due in part to the use of immunogens that appear to recapitulate responses induced naturally by HIV that are, at best, partially effective. We previously showed that the capacity of CD8+ T cells from patients to block HIV replication in culture is strongly correlated with HIV control in vivo, therefore, we investigated the virological determinants of potent CD8+ T cell inhibitory activity. We observed that CD8+ T cells from patients with naturally low plasma viral loads (viremic controllers) were better able to inhibit the replication of diverse HIV strains in vitro than CD8+ T cells from HIV-noncontroller patients. Importantly, we also found that the potency of the antiviral activity in the latter group was strongly correlated with recognition of selected regions across the viral proteome that are critical to viral fitness. Vaccines that encode full-length viral proteins rarely elicited responses to these vulnerable regions. Taken together, our results provide insight into the characteristics of effective cell-mediated immune responses against HIV and how these may inform the design of better immunogens.

Vyšlo v časopise: Identification of Effective Subdominant Anti-HIV-1 CD8+ T Cells Within Entire Post-infection and Post-vaccination Immune Responses. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004658
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004658

Souhrn

Zdroje

1. Buchbinder SP, Mehrotra D V, Duerr A, Fitzgerald DW, Mogg R, et al. (2008) Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372: 1881–1893. doi: 10.1016/S0140-6736(08)61591-3 19012954

2. McElrath MJ, De Rosa SC, Moodie Z, Dubey S, Kierstead L, et al. (2008) HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet 372: 1894–1905. doi: 10.1016/S0140-6736(08)61592-5 19012957

3. Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, et al. (2013) Efficacy Trial of a DNA/rAd5 HIV-1 Preventive Vaccine. N Engl J Med 369: 2083–2092. doi: 10.1056/NEJMoa1310566 24099601

4. Wilson NA, Keele BF, Reed JS, Piaskowski SM, MacNair CE, et al. (2009) Vaccine-induced cellular responses control simian immunodeficiency virus replication after heterologous challenge. J Virol 83: 6508–6521. doi: 10.1128/JVI.00272-09 19403685

5. Migueles SA, Rood JE, Berkley AM, Guo T, Mendoza D, et al. (2011) Trivalent adenovirus type 5 HIV recombinant vaccine primes for modest cytotoxic capacity that is greatest in humans with protective HLA class I alleles. PLoS Pathog 7: e1002002. doi: 10.1371/journal.ppat.1002002 21383976

6. Janes H, Friedrich DP, Krambrink A, Smith RJ, Kallas EG, et al. (2013) Vaccine-Induced Gag-Specific T Cells Are Associated With Reduced Viremia After HIV-1 Infection. J Infect Dis 208: 1231–1239. doi: 10.1093/infdis/jit322 23878319

7. Li F, Finnefrock AC, Dubey SA, Korber BT, Szinger J, et al. (2011) Mapping HIV-1 vaccine induced T-cell responses: bias towards less-conserved regions and potential impact on vaccine efficacy in the Step study. PLoS One 6: e20479. doi: 10.1371/journal.pone.0020479 21695251

8. Borthwick N, Ahmed T, Ondondo B, Hayes P, Rose A, et al. (2014) Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. Mol Ther 22: 464–475. doi: 10.1038/mt.2013.248 24166483

9. Gray GE, Allen M, Moodie Z, Churchyard G, Bekker L-G, et al. (2011) Safety and efficacy of the HVTN 503/Phambili Study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study. Lancet Infect Dis 11: 507–515. doi: 10.1016/s1473–3099(11)70098-6 21570355

10. Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, et al. (2007) CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 13: 46–53. 17173051

11. Zuniga R, Lucchetti A, Galvan P, Sanchez S, Sanchez C, et al. (2006) Relative Dominance of Gag p24-Specific Cytotoxic T Lymphocytes Is Associated with Human Immunodeficiency Virus Control. J Virol 80: 3122–3125. 16501126

12. Hertz T, Ahmed H, Friedrich DP, Casimiro DR, Self SG, et al. (2013) HIV-1 Vaccine-Induced T-Cell Reponses Cluster in Epitope Hotspots that Differ from Those Induced in Natural Infection with HIV-1. PLoS Pathog 9: e1003404. doi: 10.1371/journal.ppat.1003404 23818843

13. Rihn SJ, Wilson SJ, Loman NJ, Alim M, Bakker SE, et al. (2013) Extreme Genetic Fragility of the HIV-1 Capsid. PLoS Pathog 9: e1003461. doi: 10.1371/journal.ppat.1003461 23818857

14. Mothe B, Llano A, Ibarrondo J, Daniels M, Miranda C, et al. (2011) Definition of the viral targets of protective HIV-1-specific T cell responses. J Transl Med 9: 208. doi: 10.1186/1479-5876-9-208 22152067

15. Rolland M, Nickle DC, Mullins JI (2007) HIV-1 Group M Conserved Elements Vaccine. PLoS Pathog 3: e157. 18052528

16. Yang H, Wu H, Hancock G, Clutton G, Sande N, et al. (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. doi: 10.1093/infdis/jis379 22711904

17. Saez-Cirion A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, et al. (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 U S A 104: 6776–6781. 17428922

18. Julg B, Williams KL, Reddy S, Bishop K, Qi Y, et al. (2010) Enhanced anti-HIV functional activity associated with Gag-specific CD8 T-cell responses. J Virol 84: 5540–5549. doi: 10.1128/JVI.02031-09 20335261

19. Payne RP, Kløverpris H, Sacha JB, Brumme Z, Brumme C, et al. (2010) Efficacious Early Antiviral Activity of HIV Gag- and Pol-Specific HLA-B*2705-Restricted CD8+ T Cells. J Virol 84: 10543–10557. doi: 10.1128/JVI.00793-10 20686036

20. Buckheit RW, Salgado M, Silciano RF, Blankson JN (2012) Inhibitory Potential of Subpopulations of CD8+ T Cells in HIV-1-Infected Elite Suppressors. J Virol 86: 13679–13688. doi: 10.1128/jvi.02439-12 23055552

21. Freel SA, Picking RA, Ferrari G, Ding H, Ochsenbauer C, et al. (2012) Initial HIV-1 Antigen-Specific CD8+ T Cells in Acute HIV-1 Infection Inhibit Transmitted/Founder Virus Replication. J Virol 86: 6835–6846. doi: 10.1128/JVI.00437-12 22514337

22. Tomaras GD, Lacey SF, McDanal CB, Ferrari G, Weinhold KJ, et al. (2000) CD8+ T cell-mediated suppressive activity inhibits HIV-1 after virus entry with kinetics indicating effects on virus gene expression. Proc Natl Acad Sci 97: 3503–3508. doi: 10.1073/pnas.97.7.3503 10725407

23. Freel SA, Lamoreaux L, Chattopadhyay PK, Saunders K, Zarkowsky D, et al. (2010) Phenotypic and functional profile of HIV-inhibitory CD8 T cells elicited by natural infection and heterologous prime/boost vaccination. J Virol 84: 4998–5006. doi: 10.1128/JVI.00138-10 20200250

24. Lécuroux C, Girault I, Chéret A, Versmisse P, Nembot G, et al. (2013) CD8 T-Cells from Most HIV-Infected Patients Lack Ex Vivo HIV-Suppressive Capacity during Acute and Early Infection. PLoS One 8: e59767. doi: 10.1371/journal.pone.0059767 23555774

25. Streeck H, Brumme ZL, Anastario M, Cohen KW, Jolin JS, et al. (2008) Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells. PLoS Med 5: e100. doi: 10.1371/journal.pmed.0050100 18462013

26. Spentzou A, Bergin P, Gill D, Cheeseman H, Ashraf A, et al. (2010) Viral inhibition assay: a CD8 T cell neutralization assay for use in clinical trials of HIV-1 vaccine candidates. J Infect Dis 201: 720–729. doi: 10.1086/650492 20132004

27. Rolland M, Manocheewa S, Swain JV, Lanxon-Cookson EC, Kim M, et al. (2013) HIV-1 Conserved-Element Vaccines: Relationship between Sequence Conservation and Replicative Capacity. J Virol 87: 5461–5467. doi: 10.1128/JVI.03033-12 23468488

28. Kulkarni V, Rosati M, Valentin A, Ganneru B, Singh AK, et al. (2013) HIV-1 p24gag Derived Conserved Element DNA Vaccine Increases the Breadth of Immune Response in Mice. PLoS One 8: e60245. doi: 10.1371/journal.pone.0060245 23555935

29. Mothe B, Llano A, Ibarrondo J, Zamarreno J, Schiaulini M, et al. (2012) CTL responses of high functional avidity and broad variant cross-reactivity are associated with HIV control. PLoS One 7: e29717. doi: 10.1371/journal.pone.0029717 22238642

30. Brumme ZL, Brumme CJ, Carlson J, Streeck H, John M, et al. (2008) Marked Epitope- and Allele-Specific Differences in Rates of Mutation in Human Immunodeficiency Type 1 (HIV-1) Gag, Pol, and Nef Cytotoxic T-Lymphocyte Epitopes in Acute/Early HIV-1 Infection. J Virol 82: 9216–9227. doi: 10.1128/JVI.01041-08 18614631

31. Miura T, Brockman MA, Schneidewind A, Lobritz M, Pereyra F, et al. (2009) HLA-B57/B*5801 Human Immunodeficiency Virus Type 1 Elite Controllers Select for Rare Gag Variants Associated with Reduced Viral Replication Capacity and Strong Cytotoxic T-Lymphotye Recognition. J Virol 83: 2743–2755. doi: 10.1128/JVI.02265-08 19116253

32. Streeck H, Jolin JS, Qi Y, Yassine-Diab B, Johnson RC, et al. (2009) Human Immunodeficiency Virus Type 1-Specific CD8+ T-Cell Responses during Primary Infection Are Major Determinants of the Viral Set Point and Loss of CD4+ T Cells. J Virol 83: 7641–7648. doi: 10.1128/JVI.00182-09 19458000

33. Li F, Malhotra U, Gilbert PB, Hawkins NR, Duerr AC, et al. (2006) Peptide selection for human immunodeficiency virus type 1 CTL-based vaccine evaluation. Vaccine 24: 6893–6904. doi: http://dx.doi.org/10.1016/j.vaccine.2006.06.009 16890329

34. Dorrell L, Yang H, Ondondo B, Dong T, de Gleria K, et al. (2006) Expansion and diversification of virus-specific T cells following immunisation of HIV-1-infected individuals with a recombinant modified vaccinia virus Ankara / HIV-1 gag vaccine. J Virol 80: 4705–4716. 16641264

35. Hanke T, McMichael AJ (2000) Design and construction of an experimental HIV-1 vaccine for a year-2000 clinical trial in Kenya. Nat Med 6: 951–955. 10973301

36. Llano A, Williams A, Overa A, Silva-Arrieta S, Brander C (2013) HIV Molecular Immunology 2013. Yusim K, Korber B, Brander C, Barouch D, de Boer RJ, et al., editors Los Alamos National Laboratory, Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, New Mexico. doi: 10.1016/j.jfo.2013.06.003 25632406

37. Korber BT, Letvin NL, Haynes BF (2009) T-Cell Vaccine Strategies for Human Immunodeficiency Virus, the Virus with a Thousand Faces. J Virol 83: 8300–8314. doi: 10.1128/JVI.00114-09 19439471

38. Barouch DH, O’Brien KL, Simmons NL, King SL, Abbink P, et al. (2010) Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med 16: 319–323. doi: 10.1038/nm.2089 20173752

39. Letourneau S, Im EJ, Mashishi T, Brereton C, Bridgeman A, et al. (2007) Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One 2: e984. doi: 10.1371/annotation/fca26a4f-42c1-4772-a19e-aa9d96c4eeb2 17912361

40. Kopycinski J, Hayes P, Ashraf A, Cheeseman H, Lala F, et al. (2014) Broad HIV Epitope Specificity and Viral Inhibition Induced by Multigenic HIV-1 Adenovirus Subtype 35 Vector Vaccine in Healthy Uninfected Adults. PLoS One 9: e90378. doi: 10.1371/journal.pone.0090378 24609066

41. Koup RA, Safrit JT, Cao Y, Andrews C, McLeod G, et al. (1994) Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 68: 4650–4655. 8207839

42. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, et al. (1999) Control of Viremia in Simian Immunodeficiency Virus Infection by CD8+ Lymphocytes. Science (80-) 283: 857–860.

43. Goonetilleke N, Liu MKP, Salazar-Gonzalez JF, Ferrari G, Giorgi E, et al. (2009) The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med 206: 1253–1272. doi: 10.1084/jem.20090365 19487423

44. Shapiro SZ (2014) Clinical Development of Candidate HIV Vaccines: Different Problems for Different Vaccines. AIDS Res Hum Retroviruses 30: 325–329. doi: 10.1089/aid.2013.0114 24168166

45. Manocheewa S, Swain JV, Lanxon-Cookson E, Rolland M, Mullins JI (2013) Fitness Costs of Mutations at the HIV-1 Capsid Hexamerization Interface. PLoS One 8: e66065. doi: 10.1371/journal.pone.0066065 23785468

46. Streeck H, Lu R, Beckwith N, Milazzo M, Liu M, et al. (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. doi: 10.1128/JVI.02016-14 25165102

47. Pereyra F, Heckerman D, Carlson JM, Kadie C, Soghoian DZ, et al. (2014) HIV Control Is Mediated in Part by CD8+ T-Cell Targeting of Specific Epitopes. J Virol 88: 12937–12948. doi: 10.1128/JVI.01004-14 25165115

48. Ganusov V V, Goonetilleke N, Liu MKP, Ferrari G, Shaw GM, et al. (2011) Fitness Costs and Diversity of the Cytotoxic T Lymphocyte (CTL) Response Determine the Rate of CTL Escape during Acute and Chronic Phases of HIV Infection. J Virol 85: 10518–10528. doi: 10.1128/JVI.00655-11 21835793

49. Boutwell CL, Carlson JM, Lin T-H, Seese A, Power KA, et al. (2013) Frequent and Variable Cytotoxic-T-Lymphocyte Escape-Associated Fitness Costs in the Human Immunodeficiency Virus Type 1 Subtype B Gag Proteins. J Virol 87: 3952–3965. doi: 10.1128/JVI.03233-12 23365420

50. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, et al. (2006) HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107: 4781–4789. 16467198

51. Riou C, Burgers WA, Mlisana K, Koup RA, Roederer M, et al. (2014) Differential Impact of Magnitude, Polyfunctional Capacity, and Specificity of HIV-Specific CD8+ T Cell Responses on HIV Set Point. J Virol 88: 1819–1824. doi: 10.1128/JVI.02968-13 24227857

52. Stephenson KE, SanMiguel A, Simmons NL, Smith K, Lewis MG, et al. (2012) Full-Length HIV-1 Immunogens Induce Greater Magnitude and Comparable Breadth of T Lymphocyte Responses to Conserved HIV-1 Regions Compared with Conserved-Region-Only HIV-1 Immunogens in Rhesus Monkeys. J Virol 86: 11434–11440. doi: 10.1128/JVI.01779-12 22896617

53. Kulkarni V, Valentin A, Rosati M, Alicea C, Singh AK, et al. (2014) Altered Response Hierarchy and Increased T-Cell Breadth upon HIV-1 Conserved Element DNA Vaccination in Macaques. PLoS One 9: e86254. doi: 10.1371/journal.pone.0086254 24465991

54. Valkenburg SA, Gras S, Guillonneau C, Hatton LA, Bird NA, et al. (2013) Preemptive priming readily overcomes structure-based mechanisms of virus escape. Proc Natl Acad Sci 110: 5570–5575. doi: 10.1073/pnas.1302935110 23493558

55. Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, et al. (2011) Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature: Epub ahead of print.

56. Hansen SG, Sacha JB, Hughes CM, Ford JC, Burwitz BJ, et al. (2013) Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science (80-) 340: 1237874. doi: 10.1126/science.1237874 23704576

57. Hansen SG, Piatak M Jr., Ventura AB, Hughes CM, Gilbride RM, et al. (2013) Immune clearance of highly pathogenic SIV infection. Nature 502: 100–104. doi: 10.1038/nature12519 24025770

58. Liu MKP, Hawkins N, Ritchie AJ, Ganusov V V, Whale V, et al. (2013) Vertical T cell immunodominance and epitope entropy determine HIV-1 escape. J Clin Invest 123: 380–393. doi: 10.1172/JCI65330 23221345

59. Fellay J, Shianna K V, Ge D, Colombo S, Ledergerber B, et al. (2007) A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1. Science (80-) 317: 944–947.

60. Yang H, Dong T, Turnbull E, Ranasinghe S, Ondondo B, et al. (2007) Broad TCR Usage in Functional HIV-1-Specific CD8+ T Cell Expansions Driven by Vaccination during Highly Active Antiretroviral Therapy. J Immunol 179: 597–606. 17579081

61. Rolland M, Tovanabutra S, deCamp AC, Frahm N, Gilbert PB, et al. (2011) Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial. Nat Med 17: 366–371. doi: 10.1038/nm.2316 21358627

62. De Oliveira T, Deforche K, Cassol S, Salminen M, Paraskevis D, et al. (2005) An automated genotyping system for analysis of HIV-1 and other microbial sequences. Bioinforma 21: 3797–3800. doi: 10.1093/bioinformatics/bti607.

63. Alcantara LCJ, Cassol S, Libin P, Deforche K, Pybus OG, et al. (2009) A standardized framework for accurate, high-throughput genotyping of recombinant and non-recombinant viral sequences. Nucleic Acids Res 37: W634–W642. doi: 10.1093/nar/gkp455 19483099

64. Koup RA, Ho DD, Poli G, Fauci AS (2001) Isolation and quantitation of HIV in peripheral blood. Curr Protoc Immunol 5: 2.1–2.11. doi: 10.1002/0471142735.im1202s05.

65. Yang H, Yorke E, Hancock G, Clutton G, Sande N, et al. (2013) Improved quantification of HIV-1-infected CD4+ T cells using an optimised method of intracellular HIV-1 gag p24 antigen detection. J Immunol Methods 391: 174–178. doi: 10.1016/j.jim.2013.03.001 23500782

66. Horton H, Thomas EP, Stucky JA, Frank I, Moodie Z, et al. (2007) Optimization and validation of an 8-color intracellular cytokine staining (ICS) assay to quantify antigen-specific T cells induced by vaccination. J Immunol Methods 323: 39–54. doi: http://dx.doi.org/10.1016/j.jim.2007.03.002 17451739