Effects of combined antiretroviral therapy on B- and T-cell release from production sites in long-term treated HIV-1+ patients

Journal of Translational Medicine

Luisa Imberti²  Luigi Caimi²  Carlo Torti¹  Daria Gotti¹  Alessandra Sottini²  Cinzia Zanotti²  Marco Chiarini²  Federico Serana²  Eugenia Quiros-Roldan¹ 

[1] Institute of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy;Laboratory of Biotechnology, Diagnostics Department, Spedali Civili of Brescia, Brescia, Italy

关键词: B lymphocytes;    T lymphocytes;    cART;    HIV-1;    TRECs;    KRECs;   

Others  :  1205987
DOI  :  10.1186/1479-5876-10-94

 received in 2012-01-19, accepted in 2012-04-24,  发布年份 2012

【 摘 要 】

Background

The immune system reconstitution in HIV-1- infected patients undergoing combined antiretroviral therapy is routinely evaluated by T-cell phenotyping, even though the infection also impairs the B-cell mediated immunity. To find new laboratory markers of therapy effectiveness, both B- and T- immune recovery were evaluated by means of a follow-up study of long-term treated HIV-1- infected patients, with a special focus on the measure of new B- and T-lymphocyte production.

Methods

A longitudinal analysis was performed in samples obtained from HIV-1-infected patients before therapy beginning and after 6, 12, and 72 months with a duplex real-time PCR allowing the detection of K-deleting recombination excision circles (KRECs) and T-cell receptor excision circles (TRECs), as measures of bone-marrow and thymic output, respectively. A cross sectional analysis was performed to detect B- and T-cell subsets by flow cytometry in samples obtained at the end of the follow-up, which were compared to those of untreated HIV-1-infected patients and uninfected controls.

Results

The kinetics and the timings of B- and T-cell release from the bone marrow and thymus during antiretroviral therapy were substantially different, with a decreased B-cell release and an increased thymic output after the prolonged therapy. The multivariable regression analysis showed that a longer pre-therapy infection duration predicts a minor TREC increase and a major KREC reduction.

Conclusions

The quantification of KRECs and TRECs represents an improved method to monitor the effects of therapies capable of influencing the immune cell pool composition in HIV-1-infected patients.

【 授权许可】

   
2012 Quiros-Roldan et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1 .

Figure 2 .

Figure 3 .

【 参考文献 】

• [1]Belyakov IM, Berzofsky JA: Immunobiology of mucosal HIV infection and the basis for development of a new generation of mucosal AIDS vaccines. Immunity 2004, 20:247-253.
• [2]Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS: Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 1983, 309:453-458.
• [3]Malaspina A, Moir S, Kottilil S, Hallahan CW, Ehler LA, Liu S, Planta MA, Chun TW, Fauci AS: Deleterious effect of HIV-1 plasma viremia on B cell costimulatory function. J Immunol 2003, 170:5965-5972.
• [4]Martínez-Maza O, Crabb E, Mitsuyasu RT, Fahey JL, Giorgi JV: Infection with the human immunodeficiency virus (HIV) is associated with an in vivo increase in B lymphocyte activation and immaturity. J Immunol 1987, 138:3720-3724.
• [5]Amadori A, Chieco-Bianchi L: B-cell activation and HIV-1 infection: deeds and misdeeds. Immunol Today 1990, 11:374-379.
• [6]Moir S, Ogwaro KM, Malaspina A, Vasquez J, Donoghue ET, Hallahan CW, Liu S, Ehler LA, Planta MA, Kottilil S, Chun TW, Fauci AS: Perturbations in B cell responsiveness to CD4+ T cell help in HIV-infected individuals. Proc Natl Acad Sci USA 2003, 100:6057-6062.
• [7]Samuelsson A, Sönnerborg A, Heuts N, Cöster J, Chiodi F: Progressive B cell apoptosis and expression of Fas ligand during human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses 1997, 13:1031-1038.
• [8]De Milito A, Mörch C, Sönnerborg A, Chiodi F: Loss of memory (CD27) B lymphocytes in HIV-1 infection. AIDS 2001, 15:957-964.
• [9]Ho J, Moir S, Malaspina A, Howell ML, Wang W, DiPoto AC, O’Shea MA, Roby GA, Kwan R, Mican JM, Chun TW, Fauci AS: Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms. Proc Natl Acad Sci USA 2006, 103:19436-19441.
• [10]Moir S, Ho J, Malaspina A, Wang W, DiPoto AC, O’Shea MA, Roby G, Kottilil S, Arthos J, Proschan MA, Chun TW, Fauci AS: Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J Exp Med 2008, 205:1797-1805.
• [11]Nagase H, Agematsu K, Kitano K, Takamoto M, Okubo Y, Komiyama A, Sugane K: Mechanism of hypergammaglobulinemia by HIV infection: circulating memory B-cell reduction with plasmacytosis. Clin Immunol 2001, 100:250-259.
• [12]Richard Y, Amiel C, Jeantils V, Mestivier D, Portier A, Dhello G, Feuillard J, Creidy R, Nicolas JC, Raphael M: Changes in blood B cell phenotypes and Epstein-Barr virus load in chronically human immunodeficiency virus–infected patients before and after antiretroviral therapy. J Infect Dis 2010, 202:1424-1434.
• [13]Yazdanpanah Y, Fagard C, Descamps D, Taburet AM, Colin C, Roquebert B, Katlama C, Pialoux G, Jacomet C, Piketty C, Bollens D, Molina JM, Chêne G, ANRS 139 TRIO Trial Group: High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO trial. Clin Infect Dis 2009, 49:1441-1449.
• [14]Vrisekoop N, van Gent R, de Boer AB, Otto SA, Borleffs JC, Steingrover R, Prins JM, Kuijpers TW, Wolfs TF, Geelen SP, Vulto I, Lansdorp P, Tesselaar K, Borghans JA, Miedema F: Restoration of the CD4 T cell compartment after long-term highly active antiretroviral therapy without phenotypical signs of accelerated immunological aging. J Immunol 2008, 181:1573-1581.
• [15]Tan R, Westfall AO, Willig JH, Mugavero MJ, Saag MS, Kaslow RA, Kempf MC: Clinical outcome of HIV-infected antiretroviral-naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2008, 47:553-558.
• [16]Gutiérrez F, Padilla S, Masiá M, Iribarren JA, Moreno S, Viciana P, Hernández-Quero J, Alemán R, Vidal F, Salavert M, Blanco JR, Leal M, Dronda F, del Amo J, CoRIS-MD: Patients’ characteristics and clinical implications of suboptimal CD4 T-cell gains after 1 year of successful antiretroviral therapy. Curr HIV Res 2008, 6:100-107.
• [17]Antiretroviral Therapy Cohort Collaboration: Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008, 372:293-299.
• [18]Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA: Changes in thymic function with age and during the treatment of HIV infection. Nature 1998, 396:690-695.
• [19]Nobile M, Correa R, Borghans JA, D’Agostino C, Schneider P, De Boer RJ, Pantaleo G, Swiss HIV Cohort Study: De novo T-cell generation in patients at different ages and stages of HIV-1 disease. Blood 2004, 104:470-477.
• [20]Ometto L, De Forni D, Patiri F, Trouplin V, Mammano F, Giacomet V, Giaquinto C, Douek D, Koup R, De Rossi A: Immune reconstitution in HIV-1-infected children on antiretroviral therapy: role of thymic output and viral fitness. AIDS 2002, 16:839-849.
• [21]De Rossi A, Walker AS, Klein N, De Forni D, King D, Gibb DM: Increased thymic output after initiation of antiretroviral therapy in human immunodeficiency virus type 1-infected children in the Paediatric European Network for Treatment of AIDS (PENTA) 5 Trial. J Infect Dis 2002, 186:312-320.
• [22]Chavan S, Bennuri B, Kharbanda M, Chandrasekaran A, Bakshi S, Pahwa S: Evaluation of T cell receptor gene rearrangement excision circles after antiretroviral therapy in children infected with human immunodeficiency virus. J Infect Dis 2001, 183:1445-1454.
• [23]Sottini A, Ghidini C, Zanotti C, Chiarini M, Caimi L, Lanfranchi A, Moratto D, Porta F, Imberti L: Simultaneous quantification of recent thymic T-cell and bone marrow B-cell emigrants in patients with primary immunodeficiency undergone to stem cell transplantation. Clin Immunol 2010, 136:217-227.
• [24]Serana F, Sottini A, Chiarini M, Zanotti C, Ghidini C, Lanfranchi A, Notarangelo LD, Caimi L, Imberti L: The different extent of B and T cell immune reconstitution after hematopoietic stem cell transplantation and enzyme replacement therapies in SCID patients with adenosine deaminase deficiency. J Immunol 2010, 185:7713-7722.
• [25]Torti C, Quiros-Roldan ME, Cologni G, Nichelatti M, Ceresoli F, Pinti M, Nasi M, Cossarizza A, Lapadula G, Costarelli S, Manca N, Gargiulo F, Magoni M, Carosi G: Plasma HIV load and proviral DNA decreases after two standard antiretroviral regimens in HIV-positive patients naïve to antiretrovirals. Curr HIV Res 2008, 6:43-48.
• [26]Chen X, Barfield R, Benaim E, Leung W, Knowles J, Lawrence D, Otto M, Shurtleff SA, Neale GA, Behm FG, Turner V, Handgretinger R: Prediction of T-cell reconstitution by assessment of T-cell receptor excision circle before allogeneic hematopoietic stem cell transplantation in pediatric patients. Blood 2005, 105:886-893.
• [27]Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999, 401:708-712.
• [28]Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE: Identification and characterization of circulating human transitional B cells. Blood 2005, 105:4390-4398.
• [29]Kimmig S, Przybylski GK, Schmidt CA, Laurisch K, Möwes B, Radbruch A, Thiel A: Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J Exp Med 2002, 195:789-794.
• [30]Chiarini M, Sottini A, Ghidini C, Zanotti C, Serana F, Rottoli M, Zaffaroni M, Bergamaschi R, Cordioli C, Capra R, Imberti L: Renewal of the T-cell compartment in multiple sclerosis patients treated with glatiramer acetate. Mult Scler 2010, 16:218-227.
• [31]Colle JH, Moreau JL, Fontanet A, Lambotte O, Joussemet M, Delfraissy JF, Theze J: CD127 expression and regulation are altered in the memory CD8 T cells of HIV-infected patients–reversal by highly active anti-retroviral therapy (HAART). Clin Exp Immunol 2006, 143:398-403.
• [32]Koesters SA, Alimonti JB, Wachihi C, Matu L, Anzala O, Kimani J, Embree JE, Plummer FA, Fowke KR: IL-7Ralpha expression on CD4+ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation. Eur J Immunol 2006, 36:336-344.
• [33]De Milito A, Nilsson A, Titanji K, Thorstensson R, Reizenstein E, Narita M, Grutzmeier S, Sönnerborg A, Chiodi F: Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood 2004, 103:2180-2186.
• [34]Ribeiro RM, Perelson AS: Determining thymic output quantitatively: using models to interpret experimental T-cell receptor excision circle (TREC) data. Immunol Rev 2007, 216:21-34.
• [35]Lorenzi AR, Patterson AM, Pratt A, Jefferson M, Chapman CE, Ponchel F, Isaacs JD: Determination of thymic function directly from peripheral blood: a validated modification to an established method. J Immunol Methods 2008, 339:185-194.
• [36]van Zelm MC, Szczepanski T, van der Burg M, van Dongen JJ: Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion. J Exp Med 2007, 204:645-655.
• [37]Malaspina A, Moir S, Chaitt DG, Rehm CA, Kottilil S, Falloon J, Fauci AS: Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7. Blood 2007, 109:2086-2088.
• [38]Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Herzenberg LA, Herndier BG, Andersson J, McCune JM: Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med 2001, 7:73-79.
• [39]Sereti I, Dunham RM, Spritzler J, Aga E, Proschan MA, Medvik K, Battaglia CA, Landay AL, Pahwa S, Fischl MA, Asmuth DM, Tenorio AR, Altman JD, Fox L, Moir S, Malaspina A, Morre M, Buffet R, Silvestri G, Lederman MM, ACTG 5214 Study Team: IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood 2009, 113:6304-6314.
• [40]Levy Y, Sereti I, Tambussi G, Routy J, Delfraissy J, Molina J, Fischl MA, Croughs T, Sekaly R, Lederman M: INSPIRE Study: Effects of r-hIL-7 on T cell recovery and thymic output in HIV-infected patients receiving c-ART - interim analysis of a phase I/IIa multicenter study. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-1230a, 2009. [ http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=30cfb0e3-06f8-42ba-b4fb-47507d251418&cKey=c3c8cd19-6ca1-4b80-afe1-b802abba13b8&mKey={14EBFE7E-6F65-4D97-8CB6-F64F4347C38A} webcite]
• [41]Chong Y, Ikematsu H, Kikuchi K, Yamamoto M, Murata M, Nishimura M, Nabeshima S, Kashiwagi S, Hayashi J: Selective CD27+ (memory) B cell reduction and characteristic B cell alteration in drug-naive and HAART-treated HIV type 1-infected patients. AIDS Res Hum Retroviruses 2004, 20:219-226.
• [42]Benveniste O, Flahault A, Rollot F, Elbim C, Estaquier J, Pédron B, Duval X, Dereuddre-Bosquet N, Clayette P, Sterkers G, Simon A, Ameisen JC, Leport C: Mechanisms involved in the low-level regeneration of CD4+ cells in HIV-1-infected patients receiving highly active antiretroviral therapy who have prolonged undetectable plasma viral loads. J Infect Dis 2005, 191:1670-1679.
• [43]Torti C, Cologni G, Uccelli MC, Quiros-Roldan E, Imberti L, Airó P, Pirovano S, Patroni A, Tirelli V, Carosi G: Immune correlates of virological response in HIV-positive patients after highly active antiretroviral therapy (HAART). Viral Immunol 2004, 17:279-286.
• [44]Moir S, Buckner CM, Ho J, Wang W, Chen J, Waldner AJ, Posada JG, Kardava L, O’Shea MA, Kottilil S, Chun TW, Proschan MA, Fauci AS: B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy. Blood 2010, 116:5571-5579.
• [45]van Grevenynghe J, Cubas RA, Noto A, DaFonseca S, He Z, Peretz Y, Filali-Mouhim A, Dupuy FP, Procopio FA, Chomont N, Balderas RS, Said EA, Boulassel MR, Tremblay CL, Routy JP, Sékaly RP, Haddad EK: Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis. J Clin Invest 2011, 121:3877-3888.
• [46]Hodge JN, Srinivasula S, Hu Z, Read SW, Porter BO, Kim I, Mican JM, Paik C, Degrange P, Di Mascio M, Sereti I: Decreases in IL-7 levels during antiretroviral treatment of HIV infection suggest a primary mechanism of receptor-mediated clearance. Blood 2011, 118:3244-3253.
• [47]Sportès C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR, Fleisher TA, Krumlauf MC, Babb RR, Chow CK, Fry TJ, Engels J, Buffet R, Morre M, Amato RJ, Venzon DJ, Korngold R, Pecora A, Gress RE, Mackall CL: Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med 2008, 205:1701-1714.