Anti-HIV potency of T-cell responses elicited by dendritic cell therapeutic vaccination


Autoři: Mathieu Surenaud aff001;  Monica Montes aff002;  Cecilia S. Lindestam Arlehamn aff003;  Alessandro Sette aff003;  Jacques Banchereau aff002;  Karolina Palucka aff002;  Jean-Daniel Lelièvre aff001;  Christine Lacabaratz aff001;  Yves Lévy aff001
Působiště autorů: Vaccine Research Institute, INSERM U955—Université Paris-Est Créteil, Créteil, France aff001;  Baylor Institute for Immunology Research, Center for Human Vaccines, Dallas TX, United States of America aff002;  La Jolla Institute for Immunology, Department of Vaccine Discovery, La Jolla, California, United States of America aff003;  University of California San Diego, Department of Medicine, La Jolla, California, United States of America aff004;  Assistance Publique-Hôpitaux de Paris, Groupe Henri-Mondor Albert-Chenevier, Service d’Immunologie Clinique, Créteil, France aff005
Vyšlo v časopise: Anti-HIV potency of T-cell responses elicited by dendritic cell therapeutic vaccination. PLoS Pathog 15(9): e32767. doi:10.1371/journal.ppat.1008011
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008011

Souhrn

Identification and characterization of CD8+ and CD4+ T-cell epitopes elicited by HIV therapeutic vaccination is key for elucidating the nature of protective cellular responses and mechanism of the immune evasion of HIV. Here, we report the characterization of HIV-specific T-cell responses in cART (combination antiretroviral therapy) treated HIV-1 infected patients after vaccination with ex vivo-generated IFNα Dendritic Cells (DCs) loaded with LIPO-5 (HIV-1 Nef 66–97, Nef 116–145, Gag 17–35, Gag 253–284 and Pol 325–355 lipopeptides). Vaccination induced and/or expanded HIV-specific CD8+ T cells producing IFNγ, perforin, granzyme A and granzyme B, and also CD4+ T cells secreting IFNγ, IL-2 and IL-13. These responses were directed against dominant and subdominant epitopes representing all vaccine regions; Gag, Pol and Nef. Interestingly, IL-2 and IL-13 produced by CD4+ T cells were negatively correlated with the peak of viral replication following analytic treatment interruption (ATI). Epitope mapping confirmed that vaccination elicited responses against predicted T-cell epitopes, but also allowed to identify a set of 8 new HIV-1 HLA-DR-restricted CD4+ T-cell epitopes. These results may help to better design future DC therapeutic vaccines and underscore the role of vaccine-elicited CD4+ T-cell responses to achieve control of HIV replication.

Klíčová slova:

Biology and life sciences – Cell biology – Cellular types – Animal cells – Blood cells – White blood cells – T cells – Cytotoxic T cells – Immune cells – Vaccination and immunization – Microbiology – Medical microbiology – Microbial pathogens – Viral pathogens – Immunodeficiency viruses – HIV – HIV-1 – Retroviruses – Lentivirus – Organisms – Viruses – RNA viruses – Physiology – Developmental biology – Molecular development – Medicine and health sciences – Immunology – Immune system – Innate immune system – Cytokines – Immune response – Pathology and laboratory medicine – Pathogens – Public and occupational health – Preventive medicine – Immune physiology – Infectious diseases – Infectious disease control – Vaccines


Zdroje

1. UNAIDS Global HIV & AIDS statistics—2018 fact sheet. Available from: http://www.unaids.org/en/resources/fact-sheet

2. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998; 338(13):853–860. doi: 10.1056/NEJM199803263381301 9516219

3. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493–505. doi: 10.1056/NEJMoa1105243 21767103

4. Troya J, Bascuñana J. Safety and Tolerability: Current Challenges to Antiretroviral Therapy for the Long-Term Management of HIV Infection. AIDS Rev. 2016;18(3):127–137. 27651173

5. Nachega JB, Marconi VC, van Zyl GU, Gardner EM, Preiser W, Hong SY, et al. HIV treatment adherence, drug resistance, virologic failure: evolving concepts. Infect Disord Drug Targets. 2011;11(2):167–174. 21406048

6. Schouten J, Wit FW, Stolte IG, Kootstra NA, van der Valk M, Geerlings SE, et al. Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study. Clin Infect Dis. 2014;59(12):1787–1797. doi: 10.1093/cid/ciu701 25182245

7. Legarth RA, Ahlström MG, Kronborg G, Larsen CS, Pedersen C, Pedersen G, et al. Long-Term Mortality in HIV-Infected Individuals 50 Years or Older: A Nationwide, Population-Based Cohort Study. J Acquir Immune Defic Syndr. 2016;71(2):213–218. doi: 10.1097/QAI.0000000000000825 26334734

8. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278(5341):1295–1300. doi: 10.1126/science.278.5341.1295 9360927

9. García F, Plana M, Vidal C, Cruceta A, O'Brien WA, Pantaleo G, et al. Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy. AIDS. 1999;13(11):F79–86. doi: 10.1097/00002030-199907300-00002 10449278

10. Peters BS. The basis for HIV immunotherapeutic vaccines. Vaccine. 2001;20(5–6):688–705. doi: 10.1016/s0264-410x(01)00394-2 11738732

11. Engelhard VH. Structure of peptides associated with MHC class I molecules. Curr Opin Immunol. 1994;6(1):13–23. 7513522

12. Rötzschke O, Falk K. Origin, structure and motifs of naturally processed MHC class II ligands. Curr Opin Immunol. 1994;6(1):45–51. 7513525

13. He D, Kunwar P, Eskin E, Horton H, Gilbert P, Hertz T. Using HLA binding prediction algorithms for epitope mapping in HIV vaccine clinical trials. BCB '11 Proceedings of the 2nd ACM Conference on Bioinformatics, Computational Biology and Biomedicine, Chicago, Illinois—August 01–03, 2011. pp. 594–601.

14. da Silva LT, Santillo BT, de Almeida A, Duarte AJDS, Oshiro TM. Using Dendritic Cell-based immunotherapy to treat HIV: How can this strategy be improved? Front Immunol. 2018;9:2993. doi: 10.3389/fimmu.2018.02993 30619346

15. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–252. doi: 10.1038/32588 9521319

16. Cobb A, Roberts LK, Palucka AK, Mead H, Montes M, Ranganathan R, et al. Development of a HIV-1 lipopeptide antigen pulsed therapeutic dendritic cell vaccine. J Immunol Methods. 2011;365(1–2):27–37. doi: 10.1016/j.jim.2010.11.002 21093448

17. Gahéry-Ségard H, Pialoux G, Figueiredo S, Igéa C, Surenaud M, Gaston J, et al. Long-term specific immune responses induced in humans by a human immunodeficiency virus type 1 lipopeptide vaccine: characterization of CD8+-T-cell epitopes recognized. J Virol. 2003;77(20):11220–11231. doi: 10.1128/JVI.77.20.11220-11231.2003 14512570

18. Gahery H, Figueiredo S, Texier C, Pouvelle-Moratille S, Ourth L, Igea C, et al. HLA-DR-restricted peptides identified in the Nef protein can induce HIV type 1-specific IL-2/IFN-gamma-secreting CD4+ and CD4+ /CD8+ T cells in humans after lipopeptide vaccination. AIDS Res Hum Retroviruses. 2007;23(3):427–437. doi: 10.1089/aid.2006.0075 17411376

19. Salmon-Céron D, Durier C, Desaint C, Cuzin L, Surenaud M, Hamouda NB, et al. Immunogenicity and safety of an HIV-1 lipopeptide vaccine in healthy adults: a phase 2 placebo-controlled ANRS trial. AIDS. 2010;24(14):2211–2223. doi: 10.1097/QAD.0b013e32833ce566 20625264

20. Lévy Y, Thiébaut R, Montes M, Lacabaratz C, Sloan L, King B, et al. Dendritic cell-based therapeutic vaccine elicits polyfunctional HIV-specific T-cell immunity associated with control of viral load. Eur J Immunol. 2014;44(9):2802–2810. doi: 10.1002/eji.201344433 25042008

21. Jensen KK, Andreatta M, Marcatili P, Buus S, Greenbaum JA, Yan Z, et al. Improved methods for predicting peptide binding affinity to MHC class II molecules. Immunology. 2018;154(3):394–406. doi: 10.1111/imm.12889 29315598

22. Jurtz V, Paul S, Andreatta M, Marcatili P, Peters B, Nielsen M. NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data. J Immunol. 2017;199(9):3360–3368. doi: 10.4049/jimmunol.1700893 28978689

23. Nemes E, Bertoncelli L, Lugli E, Pinti M, Nasi M, Manzini L, et al. Cytotoxic granule release dominates gag-specific CD4+ T-cell response in different phases of HIV infection. AIDS. 2010;24(7):947–957. doi: 10.1097/QAD.0b013e328337b144 20179574

24. Soghoian DZ, Jessen H, Flanders M, Sierra-Davidson K, Cutler S, Pertel T, et al. HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome. Sci Transl Med. 2012;4(123):123ra25. doi: 10.1126/scitranslmed.3003165 22378925

25. Lévy Y, Gahéry-Ségard H, Durier C, Lascaux AS, Goujard C, Meiffrédy V, et al. Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patients. AIDS. 2005;19(3):279–286. 15718838

26. Figueiredo S, Charmeteau B, Surenaud M, Salmon D, Launay O, Guillet JG, et al. Memory CD8(+) T cells elicited by HIV-1 lipopeptide vaccines display similar phenotypic profiles but differences in term of magnitude and multifunctionality compared with FLU- or EBV-specific memory T cells in humans. Vaccine. 2014;32(4):492–501. doi: 10.1016/j.vaccine.2013.11.052 24291199

27. Frahm N, Yusim K, Suscovich TJ, Adams S, Sidney J, Hraber P, et al. Extensive HLA class I allele promiscuity among viral CTL epitopes. Eur J Immunol. 2007;37(9):2419–2433. doi: 10.1002/eji.200737365 17705138

28. Létourneau S, Im EJ, Mashishi T, Brereton C, Bridgeman A, Yang H, et al. Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One. 2007;2(10):e984. doi: 10.1371/annotation/fca26a4f-42c1-4772-a19e-aa9d96c4eeb2 17912361

29. Murakoshi H, Zou C, Kuse N, Akahoshi T, Chikata T, Gatanaga H, et al. CD8+ T cells specific for conserved, cross-reactive Gag epitopes with strong ability to suppress HIV-1 replication. Retrovirology. 2018;15(1):46. doi: 10.1186/s12977-018-0429-y 29970102

30. Inwoley A, Recordon-Pinson P, Dupuis M, Gaston J, Genête M, Minga A, et al. Cross-clade conservation of HIV type 1 Nef immunodominant regions recognized by CD8+ T cells of HIV type 1 CRF02_AG-infected Ivorian (West Africa). AIDS Res Hum Retroviruses. 2005;21(7):620–628. doi: 10.1089/aid.2005.21.620 16060833

31. Rowland-Jones SL, Dong T, Fowke KR, Kimani J, Krausa P, Newell H, et al. Cytotoxic T cell responses to multiple conserved HIV epitopes in HIV-resistant prostitutes in Nairobi. J Clin Invest. 1998;102(9):1758–1765. doi: 10.1172/JCI4314 9802890

32. Gloster SE, Newton P, Cornforth D, Lifson JD, Williams I, Shaw GM, et al. Association of strong virus-specific CD4 T cell responses with efficient natural control of primary HIV-1 infection. AIDS. 2004;18(5):749–755. doi: 10.1097/00002030-200403260-00005 15075509

33. Pontesilli O, Carotenuto P, Kerkhof-Garde SR, Roos MT, Keet IP, Coutinho RA, et al. Lymphoproliferative response to HIV type 1 p24 in long-term survivors of HIV type 1 infection is predictive of persistent AIDS-free infection. AIDS Res Hum Retroviruses. 1999;15(11):973–981. doi: 10.1089/088922299310485 10445809

34. Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science. 1997;278(5342):1447–1450. doi: 10.1126/science.278.5342.1447 9367954

35. Dyer WB, Zaunders JJ, Yuan FF, Wang B, Learmont JC, Geczy AF, et al. Mechanisms of HIV non-progression; robust and sustained CD4+ T-cell proliferative responses to p24 antigen correlate with control of viraemia and lack of disease progression after long-term transfusion-acquired HIV-1 infection. Retrovirology. 2008;5:112. doi: 10.1186/1742-4690-5-112 19077215

36. Younes SA, Yassine-Diab B, Dumont AR, Boulassel MR, Grossman Z, Routy JP, et al. HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J Exp Med. 2003;198(12):1909–1922. doi: 10.1084/jem.20031598 14676302

37. Lichterfeld M, Kaufmann DE, Yu XG, Mui SK, Addo MM, Johnston MN, et al. Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells. J Exp Med. 2004;200(6):701–712. doi: 10.1084/jem.20041270 15381726

38. Boaz MJ, Waters A, Murad S, Easterbrook PJ, Vyakarnam A. Presence of HIV-1 Gag-specific IFN-gamma+IL-2+ and CD28+IL-2+ CD4 T cell responses is associated with nonprogression in HIV-1 infection. J Immunol. 2002;169(11):6376–6385. doi: 10.4049/jimmunol.169.11.6376 12444145

39. Harari A, Petitpierre S, Vallelian F, Pantaleo G. Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. Blood. 2004;103(3):966–972. doi: 10.1182/blood-2003-04-1203 12958069

40. Emu B, Sinclair E, Favre D, Moretto WJ, Hsue P, Hoh R, et al. Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment. J Virol. 2005;79(22):14169–14178. doi: 10.1128/JVI.79.22.14169-14178.2005 16254352

41. Potter SJ, Lacabaratz C, Lambotte O, Perez-Patrigeon S, Vingert B, Sinet M, et al. Preserved central memory and activated effector memory CD4+ T-cell subsets in human immunodeficiency virus controllers: an ANRS EP36 study. J Virol. 2007;81(24):13904–13915. doi: 10.1128/JVI.01401-07 17928341

42. Lu W, Arraes LC, Ferreira WT, Andrieu JM. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med. 2004;10(12):1359–1365. doi: 10.1038/nm1147 15568033

43. Sauce D, Gorochov G, Larsen M. HIV-specific Th2 and Th17 responses predict HIV vaccine protection efficacy. Sci Rep. 2016;6:28129. doi: 10.1038/srep28129 27324186

44. Vaccari M, Fourati S, Gordon SN, Brown DR, Bissa M, Schifanella L, et al. HIV vaccine candidate activation of hypoxia and the inflammasome in CD14+ monocytes is associated with a decreased risk of SIVmac251 acquisition. Nat Med. 2018;24(6):847–856. doi: 10.1038/s41591-018-0025-7 29785023

45. Richert L, Hue S, Hocini H, Raimbault M, Lacabaratz C, Surenaud M, et al. Cytokine and gene transcription profiles of immune responses elicited by HIV lipopeptide vaccine in HIV-negative volunteers. AIDS. 2013;27(9):1421–1431. doi: 10.1097/QAD.0b013e32835f5b60 23759749

46. Huang Y, Pantaleo G, Tapia G, Sanchez B, Zhang L, Trondsen M, et al. Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial. EBioMedicine. 2017;24:195–204. doi: 10.1016/j.ebiom.2017.09.028 28970080

47. Montaner LJ, Doyle AG, Collin M, Herbein G, Illei P, James W, et al. Interleukin 13 inhibits human immunodeficiency virus type 1 production in primary blood-derived human macrophages in vitro. J Exp Med. 1993;178(2):743–747. doi: 10.1084/jem.178.2.743 8101865

48. Bailer RT, Holloway A, Sun J, Margolick JB, Martin M, Kostman J, et al. IL-13 and IFN-gamma secretion by activated T cells in HIV-1 infection associated with viral suppression and a lack of disease progression. J Immunol. 1999;162(12):7534–7542. 10358209

49. Papasavvas E, Sun J, Luo Q, Moore EC, Thiel B, MacGregor RR, et al. IL-13 acutely augments HIV-specific and recall responses from HIV-1-infected subjects in vitro by modulating monocytes. J Immunol. 2005;175(8):5532–5540. doi: 10.4049/jimmunol.175.8.5532 16210662

50. Ruiz-Riol M, Llano A, Ibarrondo J, Zamarreño J, Yusim K, Bach V, et al. Alternative effector-function profiling identifies broad HIV-specific T-cell responses in highly HIV-exposed individuals who remain uninfected. J Infect Dis. 2015;211(6):936–946. doi: 10.1093/infdis/jiu534 25249264

51. Wilson CC, Palmer B, Southwood S, Sidney J, Higashimoto Y, Appella E, et al. Identification and antigenicity of broadly cross-reactive and conserved human immunodeficiency virus type 1-derived helper T-lymphocyte epitopes. J Virol. 2001;75(9):4195–4207. doi: 10.1128/JVI.75.9.4195-4207.2001 11287569

52. Kaufmann DE, Bailey PM, Sidney J, Wagner B, Norris PJ, Johnston MN, et al. Comprehensive analysis of human immunodeficiency virus type 1-specific CD4 responses reveals marked immunodominance of gag and nef and the presence of broadly recognized peptides. J Virol. 2004;78(9):4463–4477. doi: 10.1128/JVI.78.9.4463-4477.2004 15078927

53. Koeppe JR, Campbell TB, Rapaport EL, Wilson CC. HIV-1-specific CD4+ T-cell responses are not associated with significant viral epitope variation in persons with persistent plasma viremia. J Acquir Immune Defic Syndr. 2006;41(2):140–148. 16394844

54. Simon GG, Hu Y, Khan AM, Zhou J, Salmon J, Chikhlikar PR, et al. Dendritic cell mediated delivery of plasmid DNA encoding LAMP/HIV-1 Gag fusion immunogen enhances T cell epitope responses in HLA DR4 transgenic mice. PLoS One. 2010;5(1):e8574. doi: 10.1371/journal.pone.0008574 20052293

55. van der Burg SH, Kwappenberg KM, Geluk A, van der Kruk M, Pontesilli O, Hovenkamp E, et al. Identification of a conserved universal Th epitope in HIV-1 reverse transcriptase that is processed and presented to HIV-specific CD4+ T cells by at least four unrelated HLA-DR molecules. J Immunol. 1999;162(1):152–160. 9886381

56. Ranasinghe S, Flanders M, Cutler S, Soghoian DZ, Ghebremichael M, Davis I, et al. HIV-specific CD4 T cell responses to different viral proteins have discordant associations with viral load and clinical outcome. J Virol. 2012;86(1):277–283. doi: 10.1128/JVI.05577-11 22031937

57. Buggert M, Norström MM, Czarnecki C, Tupin E, Luo M, Gyllensten K, et al. Characterization of HIV-specific CD4+ T cell responses against peptides selected with broad population and pathogen coverage. PLoS One. 2012;7(7):e39874. doi: 10.1371/journal.pone.0039874 22792193

58. Schieffer M, Jessen HK, Oster AF, Pissani F, Soghoian DZ, Lu R, et al. Induction of Gag-specific CD4 T cell responses during acute HIV infection is associated with improved viral control. J Virol. 2014;88(13):7357–7366. doi: 10.1128/JVI.00728-14 24741089

59. Pancré V, Delhem N, Yazdanpanah Y, Delanoye A, Delacre M, Depil S, et al. Presence of HIV-1 Nef specific CD4 T cell response is associated with non-progression in HIV-1 infection. Vaccine. 2007;25(31):5927–5937. doi: 10.1016/j.vaccine.2007.05.038 17600593

60. Solberg OD, Mack SJ, Lancaster AK, Single RM, Tsai Y, Sanchez-Mazas A, et al. Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies. Hum Immunol. 2008;69(7):443–464. doi: 10.1016/j.humimm.2008.05.001 18638659

61. Castelli FA, Szely N, Olivain A, Casartelli N, Grygar C, Schneider A, et al. Hierarchy of CD4 T cell epitopes of the ANRS Lipo5 synthetic vaccine relies on the frequencies of pre-existing peptide-specific T cells in healthy donors. J Immunol. 2013;190(11):5757–5763. doi: 10.4049/jimmunol.1300145 23636059

62. Ranasinghe S, Cutler S, Davis I, Lu R, Soghoian DZ, Qi Y, et al. Association of HLA-DRB1-restricted CD4⁺ T cell responses with HIV immune control. Nat Med. 2013;19(7):930–933. doi: 10.1038/nm.3229 23793098

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

64. Jacobson JM, Routy JP, Welles S, DeBenedette M, Tcherepanova I, Angel JB, et al. Dendritic Cell Immunotherapy for HIV-1 Infection Using Autologous HIV-1 RNA: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Acquir Immune Defic Syndr. 2016;72(1):31–38. doi: 10.1097/QAI.0000000000000926 26751016

65. Yin W, Gorvel L, Zurawski S, Li D, Ni L, Duluc D, et al. Functional Specialty of CD40 and Dendritic Cell Surface Lectins for Exogenous Antigen Presentation to CD8(+) and CD4(+) T Cells. EBioMedicine. 2016;5:46–58. doi: 10.1016/j.ebiom.2016.01.029 27077111

66. Flamar AL, Xue Y, Zurawski SM, Montes M, King B, Sloan L, et al. Targeting concatenated HIV antigens to human CD40 expands a broad repertoire of multifunctional CD4+ and CD8+ T cells. AIDS. 2013;27(13):2041–2051. doi: 10.1097/QAD.0b013e3283624305 23615121

67. Flamar AL, Bonnabau H, Zurawski S, Lacabaratz C, Montes M, Richert L, et al. HIV-1 T cell epitopes targeted to Rhesus macaque CD40 and DCIR: A comparative study of prototype dendritic cell targeting therapeutic vaccine candidates. PLoS One. 2018;13(11):e0207794. doi: 10.1371/journal.pone.0207794 30500852

68. Cheng L, Wang Q, Li G, Banga R, Ma J, Yu H, et al. TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs. J Clin Invest. 2018;128(10):4387–4396. doi: 10.1172/JCI99005 30148455

69. Pantaleo G, Levy Y. Therapeutic vaccines and immunological intervention in HIV infection: a paradigm change. Curr Opin HIV AIDS. 2016;11(6):576–584. doi: 10.1097/COH.0000000000000324 27607591

Štítky
Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens


2019 Číslo 9
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Halitóza
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se