Interleukin-2 (IL-2) and IL-7 are the most intriguing molecules in immune-based HIV infection treatment. An in vitro IL-2/IL-7 cross-talk due to IL-2-driven IL-7 receptor-α-chain (IL-7Rα) down-modulation, potentially blocking IL-7 signalling has been described. We investigated the in vivo IL-2 effect on IL-7/IL-7R system, measuring free IL-7, and IL-7Rα CD4 and CD8 in 12 HIV-positive patients enrolled in a randomized IL-2 trial.
Compared to HAART alone, IL-2 induced a parallel expansion in total and naive CD4, TRECs and IL-7 plasma levels, with no IL-7Rα CD4 and IL-7Rα CD8 changes (P>0.05), suggesting that in vivo IL-2 boosts IL-7 production without down-modulating IL-7Rα, preserving IL-7-mediated T-lymphocyte homeostatic regulation. Our data confirm the pivotal role of IL-2 and IL-7 in the regulation of T-lymphocyte homeostasis in HIV infection.
References
1.
FryT., & MackallC.Interleukin-7: from bench to clinic.Blood2002; 11: 3892–3904.
2.
LeonardW.In Type I Cytokines and Interferons and Their Receptors. Edited by PaulW. 1999; 741–744. Lippincott-Raven.
3.
NapolitanoL., GrantR., DeeksS., SchmidtD., De RosaS., HerzenbergL., HerndierB., AnderssonJ., & McCuneJ.Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis.Nature Medicine2001; 1: 73–79.
4.
IsgròA., AiutiF., MezzaromaF., FranchiF., MazzoneA., LebbaF., & AiutiA.Interleukin 7 production by bone marrow-derived stromal cells in HIV-1-infected patients during highly active antiretroviral therapy.AIDS2002; 16: 2231–2232.
5.
Ruiz-MateosE., de la RosaR., FrancoJ.M., Martinez-MoyaM., RubioA., SorianoN., Sanchez-QuijanoA., LissenE., & LealM.Endogenous IL-7 is associated with increased thymic volume in adult HIV-infected patients under highly active antiretroviral therapy.AIDS2003; 7: 947–954.
6.
SmithgallM., WongJ., CrichettK., & HaffarO.IL-7 upregulates HIV-1 replication in naturally infected peripheral blood mononuclear cells.Journal of Immunology1996; 156: 2324–2330.
7.
SteffensC., ManagliaE., LandayA., & Al-HarthiL.Interleukin-7 treated naive T-cells can be productively infected by T-cell-adapted and primary isolates of human immunodeficiency virus 1.Blood2002; 99: 3310–3318.
8.
FryT., ConnickE., FalloonJ., LedermanM., LiewehrD., SpritzlerJ., SteinbergS., WoodL., YarchoanR., ZuckermanJ., LandayA., & MackallC.A potential role for interleukin-7 in T-cell homeostasis.Blood2001; 10: 2983–2990.
9.
MacPhersonJ., FexC., Sanchez-DardonJ., Hawley-FossN., & AngelJ.Interleukin-7 receptor expression on CD8+ T cells is reduced in HIV infection and partially restored with effective antiretroviral therapy.Journal of Acquired Immune Deficiency Syndromes2001; 28: 454–457.
10.
BoutboulF., PuthierD., NguyenC., Ait MohandH., KatlamaC., CarcelainG., DebréP., HirschI., & AutranB.Systematic microarray analysis reveals counter balance between perforin and interleukin 7 receptor with progression of HIV infection.10th Conference on Retroviruses & Opportunistic Infections, Boston, Mass., USA, 10–14 February 2003. Abstract 34.
11.
CariniC., McLaneM., MayerK., & EssexM.Dysregulation of interleukin-7 receptor may generate loss of cytotoxic T cell response in human immunodeficiency virus type 1 infection.European Journal of Immunology1994; 24: 2921–2937.
12.
MarchettiG., MeroniL., VarchettaS., TerzievaV., BanderaA., ManganaroD., MolteniC., TrabattoniD., FossatiS., ClericiM., GalliM., MoroniM., FranzettiF., & GoriA.Low-dose prolonged intemittent interleukin-2 adjuvant therapy: results of a randomized trial among human immunodeficiency-virus positive patients with advanced immune impairment.Journal of Infectious Diseases2002; 186: 606–616.
13.
KatlamaC., CarcelainG., DuvivierC., ChouquetC., TubianaR., De SaM., ZaguryL., CalvezV., AutranB., & CostagliolaD.Interleukin-2 accelerates CD4 cell reconstitution in HIV-infected patients with severe immunosuppression despite highly active antiretroviral therapy: the ILSTIM study – ANRS 082.AIDS2002; 16: 2027–2034.
14.
LevyY., DurierC., KrzysiekR., RabianC., CapitantC., LascauxA-S, MichonC., OksenhendlerE., WeissL., GastautJ-A, GoujardC., RouziouxC., MaralJ., DelfraissyJ-F, EmilieD., AboulkerJ-P, & Group atAS. Effects of interleukin-2 therapy combined with highly active antiretroviral therapy on immune restoration in HIV-1 infection: a randomized controlled trial.AIDS2003; 17: 343–351.
15.
ValdezH., MitsuyasuR., LandayA., SevinA., ChanE., SpritzlerJ., KalamsS., PollardR., FaheyJ., FoxL., NamkungA., EstepS., MossR., SahnerD., & LedermanM.Interleukin-2 induces increases in CD4+ lymphocyte numbers but does not enhance responses to immunization: results of A5046s.Journal of Infectious Diseases2003; 187: 320–325.
16.
XueH-H, KovanenP., Pise-MasisonC., BergM., RadovichM., BradyJ., & LeonardW.IL-2 negatively regulates IL-7 receptor a chain expression in activated T lymphocytes.Proceedings of the National Academy of Sciences, USA2002; 21: 13759–13766.
17.
Al-HarthiL., MarchettiG., SteffensC., PoulinJ., SekalyR., & LandayA.Detection of T cell receptor circles (TRECs) as biomarkers for de novo T cell synthesis using a quantitative polymerase chain reaction-enzyme linked immunosorbent assay (PCR-ELISA).Journal of Immunology Methods2000; 237: 187–197.
18.
HazenbergM., OttoS., Cohen StuartJ., VerschurenM., BorleffsJ., BoucherC., CoutinhoR., LangeJ., Rinke de WitT., TsegayeA., van DongenJ., HamannD., de BoerR., & MiedemaF.Increased cell division but not thymic disfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection.Nature Medicine2000; 8: 1036–1042.
19.
HazenbergM., StuartJ., OttoS., BorleffsJ., BoucherC., de BoerR., MiedemaF., & HamannD.T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART).Blood2000; 1: 249–255.
20.
FryT., & MackallC.Interleukin-7: master regulator of periferal T-cell homeostasis?Trends in Immunology2001; 10: 564–571.
21.
KaechS.M., HembyS., KershE., & AhmedR.Molecular and functional profiling of memory CD8 T cell differentiation.Cell2002; 6: 837–851.
22.
VingerhoetsJ., BisalinkumiE., PenneG., ColebundersR., BosmansE., KestensL., & VanhamG.Altered receptor expression and decreased sensitivity of T-cells to the stimulatory cytokines IL-2, IL-7 and IL-12 in HIV infection.Immunology Letters1998; 1: 53–61.
23.
MussiniC., PintiM., BorghiV., NasiM., AmoricoG., MonterastelliE., MorettiL., TroianoL., EspositoR., & CossarizzaA.Features of CD4-exploders, HIV-positive patients with an optimal immune reconstitution after potent antiretroviral therapy.AIDS2002; 12: 1609–1616.
24.
KovacsJ.A., VogelS., AlbertJ.M., FalloonJ., DaveyR.T.Jr., WalkerR.E., PolisM.A., SpoonerK., MetcalfJ.A., BaselerM., FyfeG., & LaneH.C.Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus.New England Journal of Medicine1996; 18: 1350–1356.
25.
DaveyR.T.Jr., ChaittD.G., PiscitelliS.C., WellsM., KovacsJ.A., WalkerR.E., FalloonJ., PolisM.A., MetcalfJ.A., MasurH., FyfeG., & LaneH.C.Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons.Journal of Infectious Diseases1997; 4: 781–789.
26.
NobileM., CorreaR., Ellefsen-LavoieK., AschwandenE., SpasojevicM., D'AgostinoC., CodarriL., KhonkarlyM., & PantaleoG.Immunologic evidence that start of ARTcan be deferred for CD4 T-cell count <200/μl.10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, 10–14 February 2003. Abstract 355.
27.
LevyY., CapitantC., HouhouS., CarriereI., ViardJ., GoujardC., GastautJ., OksenhendlerE., BoumsellL., GomardE., RabianC., WeissL., GuilletJ., DelfraissyJ., AboulkerJ., & SeligmannM.Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group.Lancet1999; 353: 1923–1929.
28.
HenggeU.R., GoosM., EsserS., ExnerV., DottererH., WiehlerH., BorchardC., MullerK., BeckmannA., EppnerM.T., BergerA., & FiedlerM.Randomized, controlled phase II trial of subcutaneous interleukin-2 in combination with highly active antiretroviral therapy (HAART) in HIV patients.AIDS1998; 17: F225–F234.
29.
EmeryS., CapraW., CooperD., MitsuyasuR., KovacsJ., VigP., SmolskisM., SaravolatzL., Clifford LaneH., FyfeG., & CurtinP.T.Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease.Journal of Infectious Diseases2000; 182: 428–434.
30.
ArnòA., RuizL., JuanM., JouA., BalagueM., ZayatM.K., MarfilS., Martinez-PicadoJ., MartinezM.A., RomeuJ., Pujol-BorrellR., LaneC., & ClotetB.Efficacy of low-dose subcutaneous interleukin-2 to treat advanced human immunodeficiency virus type 1 in persons with <250/μL CD4 T cells and undetectable plasma virus load.Journal of Infectious Diseases1999; 1: 56–60.
31.
TangJ., NuccieB.L., RittermanI., LiesveldJ.L., AbboudC.N., & RyanD.H.TGF-beta down-regulates stromal IL-7 secretion and inhibits proliferation of human B cell precursors.Journal of Immunology1997; 1: 117–125.
