Decreased HIV-Specific T-Regulatory Responses Are Associated with Effective DC-Vaccine Induced Immunity

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Highly active antiretroviral therapy (HAART) has considerably decreased AIDS-related mortality and morbidity in recent years. Nevertheless, the search for effective vaccine to combat HIV is in the limelight of modern medical research. In clinical trial settings, T-cell responses are routinely measured following vaccinations. However, the measurement of antigen-specific regulatory T-cell (Tregs) responses is omitted most of the time, since their detection is not possible with the use of standard assays. Following a phase I clinical trial in which autologous dendritic-cells pulsed with HIV-lipopeptides were used to induce T-cell responses, we used a novel assay to detect a whole range of T-helper responses, including Tregs. We report very high levels of HIV-specific Tregs responses in infected patients and interestingly, we observed that the dendritic cell-based vaccine shifted the responses from regulatory to effector phenotype, which impact on the magnitude of viral rebound after treatment interruption.

Vyšlo v časopise: Decreased HIV-Specific T-Regulatory Responses Are Associated with Effective DC-Vaccine Induced Immunity. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004752
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004752

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Zdroje

1. DAD Study Group, Friis-Møller N, Reiss P, Sabin CA, Weber R, et al. (2007) Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 356 : 1723–1735. doi: 10.1056/NEJMoa062744 17460226

2. Cazanave C, Dupon M, Lavignolle-Aurillac V, Barthe N, Lawson-Ayayi S, et al. (2008) Reduced bone mineral density in HIV-infected patients: prevalence and associated factors. AIDS 22 : 395–402. doi: 10.1097/QAD.0b013e3282f423dd 18195566

3. Bonnet F, Amieva H, Marquant F, Bernard C, Bruyand M, et al. (2013) Cognitive disorders in HIV-infected patients: are they HIV-related? AIDS 27 : 391–400. doi: 10.1097/QAD.0b013e32835b1019 23079813

4. McMichael AJ (2006) HIV vaccines. Annu Rev Immunol 24 : 227–255. doi: 10.1146/annurev.immunol.24.021605.090605 16551249

5. Fauci AS, Johnston MI, Dieffenbach CW, Burton DR, Hammer SM, et al. (2008) HIV vaccine research: the way forward. Science 321 : 530–532. doi: 10.1126/science.1161000 18653883

6. Appay V (2009) 25 years of HIV research!… and what about a vaccine? Eur J Immunol 39 : 1999–2003. doi: 10.1002/eji.200939551 19672891

7. Lévy Y, Gahéry-Ségard H, Durier C, Lascaux A-S, Goujard C, et al. (2005) Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patients. AIDS 19 : 279–286. 15718838

8. Lévy Y, Durier C, Lascaux A-S, Meiffrédy V, Gahéry-Ségard H, et al. (2006) Sustained control of viremia following therapeutic immunization in chronically HIV-1-infected individuals. AIDS 20 : 405–413. doi: 10.1097/01.aids.0000206504.09159.d3 16439874

9. Hansen SG, Vieville C, Whizin N, Coyne-Johnson L, Siess DC, et al. (2009) Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat Med 15 : 293–299. doi: 10.1038/nm.1935 19219024

10. 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 473 : 523–527. doi: 10.1038/nature10003 21562493

11. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392 : 245–252. doi: 10.1038/32588 9521319

12. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, et al. (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18 : 767–811. doi: 10.1146/annurev.immunol.18.1.767 10837075

13. Palucka K, Banchereau J (2013) Human dendritic cell subsets in vaccination. Curr Opin Immunol 25 : 396–402. doi: 10.1016/j.coi.2013.05.001 23725656

14. García F, Routy J-P (2011) Challenges in dendritic cells-based therapeutic vaccination in HIV-1 infection Workshop in dendritic cell-based vaccine clinical trials in HIV-1. Vaccine 29 : 6454–6463. doi: 10.1016/j.vaccine.2011.07.043 21791232

15. Lu W, Arraes LC, Ferreira WT, Andrieu J-M (2004) Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med 10 : 1359–1365. doi: 10.1038/nm1147 15568033

16. Van Gulck E, Vlieghe E, Vekemans M, Van Tendeloo VFI, Van De Velde A, et al. (2012) mRNA-based dendritic cell vaccination induces potent antiviral T-cell responses in HIV-1-infected patients. AIDS 26: F1–12. doi: 10.1097/QAD.0b013e32834f33e8 22156965

17. García F, Climent N, Guardo AC, Gil C, León A, et al. (2013) A dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication. Sci Transl Med 5 : 166ra2. doi: 10.1126/scitranslmed.3004682 23283367

18. Lévy Y, Thiébaut R, Montes M, Lacabaratz C, Sloan L, et al. (2014) Dendritic cell-based therapeutic vaccine elicits polyfunctional HIV-specific T-cell immunity associated with control of viral load. Eur J Immunol 44 : 2802–2810. doi: 10.1002/eji.201344433 25042008

19. Weiss L, Donkova-Petrini V, Caccavelli L, Balbo M, Carbonneil C, et al. (2004) Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood 104 : 3249–3256. doi: 10.1182/blood-2004-01-0365 15271794

20. Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, et al. (1998) Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 10 : 1969–1980. 9885918

21. Zaunders JJ, Munier ML, Seddiki N, Pett S, Ip S, et al. (2009) High levels of human antigen-specific CD4+ T cells in peripheral blood revealed by stimulated coexpression of CD25 and CD134 (OX40). J Immunol 183 : 2827–2836. doi: 10.4049/jimmunol.0803548 19635903

22. Seddiki N, Cook L, Hsu DC, Phetsouphanh C, Brown K, et al. (2014) Human antigen-specific CD4+CD25+CD134+CD39+ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses. Eur J Immunol: n/a–n/a. doi: 10.1002/eji.201344102

23. Croft M (2010) Control of Immunity by the TNFR-Related Molecule OX40 (CD134). Annu Rev Immunol 28 : 57–78. doi: 10.1146/annurev-immunol-030409-101243 20307208

24. Chattopadhyay PK, Yu J, Roederer M (2006) Live-cell assay to detect antigen-specific CD4+ T-cell responses by CD154 expression. Nat Protocols 1 : 1–6. doi: 10.1038/nprot.2006.1

25. Phetsouphanh C, Xu Y, Amin J, Seddiki N, Procopio F, et al. (2013) Characterization of transcription factor phenotypes within antigen-specific CD4+ T cells using qualitative multiplex single-cell RT-PCR. PLoS ONE 8: e74946. doi: 10.1371/journal.pone.0074946 24124462

26. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, et al. (2010) Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 184 : 3433–3441. doi: 10.4049/jimmunol.0904028 20181882

27. Himmel ME, MacDonald KG, Garcia RV, Steiner TS, Levings MK (2013) Helios+ and Helios -⁠ cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J Immunol 190 : 2001–2008. doi: 10.4049/jimmunol.1201379 23359504

28. Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, et al. (2007) Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 19 : 345–354. doi: 10.1093/intimm/dxm014 17329235

29. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, et al. (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30 : 899–911. doi: 10.1016/j.immuni.2009.03.019 19464196

30. McMurchy AN, Levings MK (2012) Suppression assays with human T regulatory cells: a technical guide. Eur J Immunol 42 : 27–34. doi: 10.1002/eji.201141651 22161814

31. Brezar V, Ruffin N, Lévy Y, Seddiki N (2014) A highly relevant and efficient single step method for simultaneous depletion and isolation of human regulatory T cells in a clinical setting. J Immunol Methods. doi: 10.1016/j.jim.2014.06.003

32. Maeda Y, Nishikawa H, Sugiyama D, Ha D, Hamaguchi M, et al. (2014) Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals. Science 346 : 1536–1540. doi: 10.1126/science.aaa1292 25525252

33. Chevalier MF, Jülg B, Pyo A, Flanders M, Ranasinghe S, et al. (2011) HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function. J Virol 85 : 733–741. doi: 10.1128/JVI.02030-10 21047960

34. Norris PJ, Moffett HF, Yang OO, Kaufmann DE, Clark MJ, et al. (2004) Beyond help: direct effector functions of human immunodeficiency virus type 1-specific CD4(+) T cells. J Virol 78 : 8844–8851. doi: 10.1128/JVI.78.16.8844-8851.2004 15280492

35. Stockinger B, Bourgeois C, Kassiotis G (2006) CD4+ memory T cells: functional differentiation and homeostasis. Immunol Rev 211 : 39–48. doi: 10.1111/j.0105-2896.2006.00381 16824115

36. Seddiki N, Brezar V, Draenert R (2014) Cell exhaustion in HIV-1 infection: role of suppressor cells. Curr Opin HIV AIDS. doi: 10.1097/COH.0000000000000087

37. Welters MJP, Kenter GG, De Vos van Steenwijk PJ, Löwik MJG, Berends-van der Meer DMA, et al. (2010) Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses. Proc Natl Acad Sci USA 107 : 11895–11899. doi: 10.1073/pnas.1006500107 20547850

38. Sugiyama D, Nishikawa H, Maeda Y, Nishioka M, Tanemura A, et al. (2013) Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci USA 110 : 17945–17950. doi: 10.1073/pnas.1316796110 24127572

39. Macatangay BJC, Szajnik ME, Whiteside TL, Riddler SA, Rinaldo CR (2010) Regulatory T cell suppression of Gag-specific CD8 T cell polyfunctional response after therapeutic vaccination of HIV-1-infected patients on ART. PLoS ONE 5: e9852. doi: 10.1371/journal.pone.0009852 20352042

40. Angin M, King M, Altfeld M, Walker BD, Wucherpfennig KW, et al. (2012) Identification of HIV-1-specific regulatory T-cells using HLA class II tetramers. AIDS 26 : 2112–2115. doi: 10.1097/QAD.0b013e328358cc75 22874519

41. Sutmuller RPM, Den Brok MHMGM, Kramer M, Bennink EJ, Toonen LWJ, et al. (2006) Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 116 : 485–494. doi: 10.1172/JCI25439 16424940

42. Liu H, Komai-Koma M, Xu D, Liew FY (2006) Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA 103 : 7048–7053. doi: 10.1073/pnas.0601554103 16632602

43. Sierro SR, Donda A, Perret R, Guillaume P, Yagita H, et al. (2011) Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity. Eur J Immunol 41 : 2217–2228. doi: 10.1002/eji.201041235 21538347

44. Pen JJ, Keersmaecker BD, Heirman C, Corthals J, Liechtenstein T, et al. (2014) Interference with PD-L1/PD-1 co-stimulation during antigen presentation enhances the multifunctionality of antigen-specific T cells. Gene Ther 21 : 262–271. doi: 10.1038/gt.2013.80 24401835

45. Cobb A, Roberts LK, Palucka AK, Mead H, Montes M, et al. (2011) Development of a HIV-1 lipopeptide antigen pulsed therapeutic dendritic cell vaccine. J Immunol Methods 365 : 27–37. doi: 10.1016/j.jim.2010.11.002 21093448

46. Wittkowski KM, Lee E, Nussbaum R, Chamian FN, Krueger JG (2004) Combining several ordinal measures in clinical studies. Stat Med 23 : 1579–1592. doi: 10.1002/sim.1778 15122738