Naïve/Effector CD4 T cell ratio as a useful predictive marker of immune reconstitution in late presenter HIV patients: A multicenter study
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Veronica Bordoni aff001; Bruno Brando aff002; Pierluca Piselli aff001; Olindo Forini aff001; Federico Enrico Perna aff003; Umberto Atripaldi aff004; Sara Carputo aff004; Federica Garziano aff004; Elisabetta Trento aff005; Giovanna D’Agosto aff005; Alessandra Latini aff005; Manuela Colafigli aff005; Antonio Cristaudo aff005; Alessandra Sacchi aff001; Massimo Andreoni aff006; Gabriella De Carli aff007; Nicoletta Orchi aff007; Sandro Grelli aff008; Arianna Gatti aff002; Carlotta Cerva aff009; Antonella Minutolo aff009; Marina Potestà aff009; Maria Luisa Di Martino aff010; Francesco Ortu aff011; Paola Selva aff012; Laura Del Pup aff013; Irene Guarnori aff014; Patrizia Lorenzini aff007; Giusy Capuano aff015; Andrea Antinori aff007; Chiara Agrati aff001
Působiště autorů:
INMI L. Spallanzani IRCCS, Rome, Italy
aff001; Blood Transfusion Center, Legnano General Hospital, Legnano, Italy
aff002; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
aff003; Department of Clinical Biochemistry, Ospedali dei Colli, Naples, Italy
aff004; San Gallicano Dermatological Institute IRCCS, Rome, Italy
aff005; Clinical Infectious Diseases, Department of System Medicine, University of Rome “Tor Vergata”, Rome, Italy
aff006; Clinical Department, INMI L Spallanzani IRCCS, Rome, Italy
aff007; Clinical Microbiology and Virology Unit, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy
aff008; General Pathology and Immunology, Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
aff009; Laboratorio di Allergologia e Diagnostica dell'HIV della S.C. Medicina Interna, Azienda Ospedaliero Universitaria Cagliari, Cagliari, Italy
aff010; Dipartimento di Medicina, Azienda Ospedaliero Universitaria Cagliari, Cagliari, Cagliari, Italy
aff011; Laboratorio Unico Metropolitano (LUM), Azienda USL, Bologna, Italy
aff012; UOC Anatomia Patologica, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
aff013; Department of Transfusion Medicine and Hematology, Azienda Ospedaliera della Provincia di Lecco, Alessandro Manzoni Hospital, Lecco, Italy
aff014; Becton Dickinson Italia, Milan, Italy
aff015
Vyšlo v časopise:
PLoS ONE 14(12)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0225415
Souhrn
A significant proportion of HIV-infected patients experiencing a late diagnosis highlights the need to define immunological protocols able to help the clinicians in identifying patients at higher risk for immunological failure. The aim of the study was to evaluate the feasibility of easy cytometric tests in defining the effect of antiretroviral treatment (cART) on immunological homeostasis and in identifying predictive markers of early immune recovery. Chronic HIV infected patients (n = 202) were enrolled in a prospective multicentric study, and their immunological profile was studied before (w0) and after 24 weeks (w24) of antiretroviral treatment (cART) using a standardized flow cytometric panel. Based on CD4 T cell count before treatment, patients were divided in late (LP: CD4 <350/mmc), intermediate (IP: 350/mmc<CD4<500/mmc) and early (EP: CD4 >500/mmc) presenters. In all groups, cART introduction increased CD4 and CD4/CD8 T cell ratio, naïve T cell (CD4 and CD8) and CD127-expressing CD4 T cells. In parallel, cART significantly reduced effector memory T cells (CD4 and CD8) and T cell activation (CD38+CD8 and CD95+CD4 T cells). Moreover, the frequency of Naïve and Effector CD4 T cells before treatment correlated with several immune parameters key associated with the pathogenesis of HIV, thus mirroring the health of immune system. Interestingly, we identified the Naïve/Effector CD4 T cell ratio (N/EM) at w0 as a marker able to predict early immune recovery. Specifically, in LP, N/EM ratio was significantly higher in immunological responder patients (CD4>500/mmc at w24) when compared to immunological non responder (CD4 T cells <500/mmc at w24). Finally, a multivariate analysis indicates that after 24w patients with N/EM ratio higher than 1.86 at w0 recovered 96 CD4 T cells more than those with N/EM ratio lower than 0.46. Altogether, our data define an easy protocol able to define reliable immunological markers useful for the characterization of immune profile in viremic HIV patients and identify the naïve/effector CD4 T cell ratio as a new tool able to predict an early immune reconstitution potential.
Klíčová slova:
Cell enumeration techniques – Cytotoxic T cells – HIV diagnosis and management – HIV infections – Immune response – T cells – T helper cells
Zdroje
1. Lederman MM, Calabrese L, Funderburg NT, Clagett B, Medvik K, Bonilla H, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis. 2011;204: 1217–1226. doi: 10.1093/infdis/jir507 21917895
2. Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection. Blood. 2011;117: 5582–5590. doi: 10.1182/blood-2010-12-322453 21403129
3. Lapadula G, Cozzi-Lepri A, Marchetti G, Antinori A, Chiodera A, Nicastri E, et al. Risk of clinical progression among patients with immunological nonresponse despite virological suppression after combination antiretroviral treatment. AIDS. 2013;27: 769–779. doi: 10.1097/QAD.0b013e32835cb747 23719349
4. Baker JV, Peng G, Rapkin J, Abrams DI, Silverberg MJ, MacArthur RD, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008;22: 841–848. doi: 10.1097/QAD.0b013e3282f7cb76 18427202
5. Lewden C, Chene G, Morlat P, Raffi F, Dupon M, Dellamonica P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr. 2007;46: 72–77. doi: 10.1097/QAI.0b013e318134257a 17621240
6. Kaufmann GR, Furrer H, Ledergerber B, Perrin L, Opravil M, Vernazza P, et al. Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Dis 41: 361–372. doi: 10.1086/431484 16007534
7. D'Amico R, Yang Y, Mildvan D, Evans SR, Schnizlein-Bick CT, Hafner R, et al. Lower CD4+ T lymphocyte nadirs may indicate limited immune reconstitution in HIV-1 infected individuals on potent antiretroviral therapy: analysis of immunophenotypic marker results of AACTG 5067. J Clin Immunol. 2005;25: 106–115. doi: 10.1007/s10875-005-2816-0 15821887
8. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. 2007;44: 441–446. doi: 10.1086/510746 17205456
9. Mussini C, Lorenzini P, Cozzi-Lepri A, Lapadula G, Marchetti G, Nicastri E, et al. CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study. Lancet HIV. 2015;2: e98–106. doi: 10.1016/S2352-3018(15)00006-5 26424550
10. Rosado-Sanchez I, Herrero-Fernandez I, Alvarez-Rios AI, Genebat M, Abad-Carrillo MA, Ruiz-Mateos E, et al. A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects. Antimicrob Agents Chemother. 2017;61: doi: 10.1128/AAC.00605-17 Print 2017 Aug.
11. Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog. 2014;10: e1004078. doi: 10.1371/journal.ppat.1004078 24831517
12. Bellissimo F, Pinzone MR, Celesia BM, Cacopardo B, Nunnari G. Baseline CD4/CD8 T-Cell Ratio Predicts Prompt Immune Restoration Upon cART Initiation. Curr HIV Res. 2016;14: 491–496. doi: 10.2174/1570162x14666160414111554 27074946
13. Schacker TW, Bosch RJ, Bennett K, Pollard R, Robbins GK, Collier AC, et al. Measurement of naive CD4 cells reliably predicts potential for immune reconstitution in HIV. J Acquir Immune Defic Syndr. 2010;54: 59–62. doi: 10.1097/QAI.0b013e3181c96520 20182359
14. Shive CL, Mudd JC, Funderburg NT, Sieg SF, Kyi B, Bazdar DA, et al. Inflammatory cytokines drive CD4+ T-cell cycling and impaired responsiveness to interleukin 7: implications for immune failure in HIV disease. J Infect Dis. 2014;210: 619–629. doi: 10.1093/infdis/jiu125 24585897
15. Shive CL, Clagett B, McCausland MR, Mudd JC, Funderburg NT, Freeman ML, et al. Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection. J Acquir Immune Defic Syndr. 2016;71: 483–492. doi: 10.1097/QAI.0000000000000913 26627102
16. Marziali M, De Santis W, Carello R, Leti W, Esposito A, Isgro A, et al. T-cell homeostasis alteration in HIV-1 infected subjects with low CD4 T-cell count despite undetectable virus load during HAART. AIDS. 2006;20: 2033–2041. doi: 10.1097/01.aids.0000247588.69438.fd 17053349
17. Nguyen TP, Shukla S, Asaad R, Freeman ML, Lederman MM, Harding CV, et al. Responsiveness to IL-7 but not to IFN-alpha is diminished in CD4+ T cells from treated HIV infected patients who experience poor CD4+ T-cell recovery. AIDS. 2016;30: 2033–2042. doi: 10.1097/QAD.0000000000001161 27191978
18. Casetti R, Pinnetti C, Sacchi A, De Simone G, Bordoni V, Cimini E, et al. HIV-Specific CD8 T Cells Producing CCL-4 Are Associated With Worse Immune Reconstitution During Chronic Infection. J Acquir Immune Defic Syndr. 2017;75: 338–344. doi: 10.1097/QAI.0000000000001392 28418988
19. Lu W, Feng Y, Jing F, Han Y, Lyu N, Liu F, et al. Association Between Gut Microbiota and CD4 Recovery in HIV-1 Infected Patients. Front Microbiol. 2018;9: 1451. doi: 10.3389/fmicb.2018.01451 30034377
20. Bordoni V, Casetti R, Capuano G, De Stefani B, Piselli P, Gioia C, et al. A novel 8-color flow cytometry panel to study activation, maturation and senescence of CD4 and CD8 T lymphocytes in HIV-infected individuals at different stages of disease. Int J Immunopathol Pharmacol. 2012;25: 415–424. doi: 10.1177/039463201202500211 22697073
21. Bordoni V, Agrati C, Rinaldi A, Viola D, De Simone G, Gioia C, et al. In HIV-infected patients, some differential alterations of CD4 and CD8 T cell homeostasis may not be restored by >/ = 7 years of highly active antiretroviral therapy, in spite of good CD4 T cell repopulation. J Antimicrob Chemother. 2012;67: 1802–1804. doi: 10.1093/jac/dks099 22461310
22. Chahroudi A, Silvestri G, Lichterfeld M. T memory stem cells and HIV: a long-term relationship. Curr HIV/AIDS Rep. 2015;12: 33–40.
23. INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373: 795–807. doi: 10.1056/NEJMoa1506816 26192873
24. Ford N, Doherty M. The Enduring Challenge of Advanced HIV Infection. N Engl J Med. 2017;377: 283–284. doi: 10.1056/NEJMe1707598 28723319
25. Tanko RF, Soares AP, Masson L, Garrett NJ, Samsunder N, Abdool Karim Q, et al. Residual T cell activation and skewed CD8+ T cell memory differentiation despite antiretroviral therapy-induced HIV suppression. Clin Immunol. 2018;195: 127–138. doi: 10.1016/j.clim.2018.06.001 29883708
26. Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW. Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol. 2013;119: 51–83. doi: 10.1016/B978-0-12-407707-2.00002-3 23886064
27. de Armas LR, Pallikkuth S, George V, Rinaldi S, Pahwa R, Arheart KL, et al. Reevaluation of immune activation in the era of cART and an aging HIV-infected population. JCI Insight. 2017;2: doi: 10.1172/jci.insight.95726
28. Hunt PW, Carrington M. Host genetic determinants of HIV pathogenesis: an immunologic perspective. Curr Opin HIV AIDS. 2008;3: 342–348. doi: 10.1097/COH.0b013e3282fbaa92 19372988
29. Schluns KS, Kieper WC, Jameson SC, Lefrancois L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol. 2000;1: 426–432. doi: 10.1038/80868 11062503
30. Tan JT, Dudl E, LeRoy E, Murray R, Sprent J, Weinberg KI, et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci U S A. 2001;98: 8732–8737. doi: 10.1073/pnas.161126098 11447288
31. Crawley AM, Angel JB. The influence of HIV on CD127 expression and its potential implications for IL-7 therapy. Semin Immunol. 2012;24: 231–240. doi: 10.1016/j.smim.2012.02.006 22421574
32. Bai F, Bellistri GM, Tincati C, Savoldi A, Pandolfo A, Bini T, et al. Reduced CD127 expression on peripheral CD4+ T cells impairs immunological recovery in course of suppressive highly active antiretroviral therapy. AIDS. 2010;24: 2590–2593. doi: 10.1097/QAD.0b013e32833f9d64 20935556
33. Guo FP, Li YJ, Qiu ZF, Lv W, Han Y, Xie J, et al. Baseline Naive CD4+ T-cell Level Predicting Immune Reconstitution in Treated HIV-infected Late Presenters. Chin Med J (Engl). 2016;129: 2683–2690.
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PLOS One
2019 Číslo 12
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