Decreases in Colonic and Systemic Inflammation in Chronic HIV Infection after IL-7 Administration

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Despite antiretroviral therapy (ART), some HIV-infected persons maintain lower than normal CD4⁺ T-cell counts in peripheral blood and in the gut mucosa. This incomplete immune restoration is associated with higher levels of immune activation manifested by high systemic levels of biomarkers, including sCD14 and D-dimer, that are independent predictors of morbidity and mortality in HIV infection. In this 12-week, single-arm, open-label study, we tested the efficacy of IL-7 adjunctive therapy on T-cell reconstitution in peripheral blood and gut mucosa in 23 ART suppressed HIV-infected patients with incomplete CD4⁺ T-cell recovery, using one cycle (consisting of three subcutaneous injections) of recombinant human IL-7 (r-hIL-7) at 20 µg/kg. IL-7 administration led to increases of both CD4⁺ and CD8⁺ T-cells in peripheral blood, and importantly an expansion of T-cells expressing the gut homing integrin α4β7. Participants who underwent rectosigmoid biopsies at study baseline and after treatment had T-cell increases in the gut mucosa measured by both flow cytometry and immunohistochemistry. IL-7 therapy also resulted in apparent improvement in gut barrier integrity as measured by decreased neutrophil infiltration in the rectosigmoid lamina propria 12 weeks after IL-7 administration. This was also accompanied by decreased TNF and increased FOXP3 expression in the lamina propria. Plasma levels of sCD14 and D-dimer, indicative of systemic inflammation, decreased after r-hIL-7. Increases of colonic mucosal T-cells correlated strongly with the decreased systemic levels of sCD14, the LPS coreceptor -⁠ a marker of monocyte activation. Furthermore, the proportion of inflammatory monocytes expressing CCR2 was decreased, as was the basal IL-1β production of peripheral blood monocytes. These data suggest that administration of r-hIL-7 improves the gut mucosal abnormalities of chronic HIV infection and attenuates the systemic inflammatory and coagulation abnormalities that have been linked to it.

Vyšlo v časopise: Decreases in Colonic and Systemic Inflammation in Chronic HIV Infection after IL-7 Administration. PLoS Pathog 10(1): e32767. doi:10.1371/journal.ppat.1003890
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003890

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Zdroje

1. BrenchleyJM, DouekDC (2008) HIV infection and the gastrointestinal immune system. Mucosal Immunol 1 : 23–30.

2. ArthosJ, CicalaC, MartinelliE, MacleodK, Van RykD, et al. (2008) HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 9 : 301–309.

3. WaclecheVS, ChomontN, GosselinA, MonteiroP, GoupilM, et al. (2012) The colocalization potential of HIV-specific CD8+ and CD4+ T-cells is mediated by integrin beta7 but not CCR6 and regulated by retinoic acid. PloS one 7: e32964.

4. BrenchleyJM, PriceDA, SchackerTW, AsherTE, SilvestriG, et al. (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12 : 1365–1371.

5. GuadalupeM, ReayE, SankaranS, PrindivilleT, FlammJ, et al. (2003) Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol 77 : 11708–11717.

6. JiangW, LedermanMM, HuntP, SiegSF, HaleyK, et al. (2009) Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 199 : 1177–1185.

7. SandlerNG, WandH, RoqueA, LawM, NasonMC, et al. (2011) Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 203 : 780–790.

8. NeuhausJ, JacobsDRJr, BakerJV, CalmyA, DuprezD, et al. (2010) Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis 201 : 1788–1795.

9. KullerLH, TracyR, BellosoW, De WitS, DrummondF, et al. (2008) Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 5: e203.

10. MacalM, SankaranS, ChunTW, ReayE, FlammJ, et al. (2008) Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses. Mucosal Immunol 1 : 475–488.

11. CicconeEJ, ReadSW, MannonPJ, YaoMD, HodgeJN, et al. (2010) Cycling of gut mucosal CD4+ T cells decreases after prolonged anti-retroviral therapy and is associated with plasma LPS levels. Mucosal immunology 3 : 172–181.

12. MavignerM, CazabatM, DuboisM, L'FaqihiFE, RequenaM, et al. (2012) Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J Clin Invest 122 : 62–69.

13. KunkelEJ, CampbellDJ, ButcherEC (2003) Chemokines in lymphocyte trafficking and intestinal immunity. Microcirculation 10 : 313–323.

14. GuaraldiG, OrlandoG, ZonaS, MenozziM, CarliF, et al. (2011) Premature age-related comorbidities among HIV-infected persons compared with the general population. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 53 : 1120–1126.

15. GuihotA, BourgaritA, CarcelainG, AutranB (2011) Immune reconstitution after a decade of combined antiretroviral therapies for human immunodeficiency virus. Trends in immunology 32 : 131–137.

16. LapadulaG, Cozzi-LepriA, MarchettiG, AntinoriA, ChioderaA, et al. (2013) Risk of Clinical Progression among patients with immunological non response despite virological suppression after combination antiretroviral treatment. AIDS 27.

17. AbramsD, LevyY, LossoMH, BabikerA, CollinsG, et al. (2009) Interleukin-2 therapy in patients with HIV infection. The New England journal of medicine 361 : 1548–1559.

18. ReadSW, CicconeEJ, MannonPJ, YaoMD, ChairezCL, et al. (2011) The effect of intermittent IL-2 therapy on CD4 T cells in the gut in HIV-1-infected patients. J Acquir Immune Defic Syndr 56 : 340–343.

19. SeretiI, ImamichiH, NatarajanV, ImamichiT, RamchandaniMS, et al. (2005) In vivo expansion of CD4CD45RO-CD25 T cells expressing foxP3 in IL-2-treated HIV-infected patients. J Clin Invest 115 : 1839–1847.

20. PorterBO, OuedraogoGL, HodgeJN, SmithMA, PauA, et al. (2010) d-Dimer and CRP levels are elevated prior to antiretroviral treatment in patients who develop IRIS. Clin Immunol 136 : 42–50.

21. LevyY, SeretiI, TambussiG, RoutyJP, LelievreJD, et al. (2012) Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 55 : 291–300.

22. LevyY, LacabaratzC, WeissL, ViardJP, GoujardC, et al. (2009) Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest 119 : 997–1007.

23. SeretiI, DunhamRM, SpritzlerJ, AgaE, ProschanMA, et al. (2009) IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood 113 : 6304–6314.

24. BeqS, RozlanS, GautierD, ParkerR, MerssemanV, et al. (2009) Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques. Blood 114 : 816–825.

25. CimbroR, VassenaL, ArthosJ, CicalaC, KehrlJH, et al. (2012) IL-7 induces expression and activation of integrin alpha4beta7 promoting naive T-cell homing to the intestinal mucosa. Blood 120 : 2610–2619.

26. LevyY, SeretiI, TambussiG, RoutyJP, LelievreJD, et al. (2012) Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study. Clin Infect Dis 55 : 291–300.

27. SchackerTW, BrenchleyJM, BeilmanGJ, ReillyC, PambuccianSE, et al. (2006) Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol 13 : 556–560.

28. EstesJD, HarrisLD, KlattNR, TabbB, PittalugaS, et al. (2010) Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog 6: e1001052.

29. SportesC, HakimFT, MemonSA, ZhangH, ChuaKS, et al. (2008) Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med 205 : 1701–1714.

30. MehandruS, PolesMA, Tenner-RaczK, Jean-PierreP, ManuelliV, et al. (2006) Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med 3: e484.

31. ChaudhryA, RudraD, TreutingP, SamsteinRM, LiangY, et al. (2009) CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326 : 986–991.

32. OlsenT, GollR, CuiG, HusebekkA, VonenB, et al. (2007) Tissue levels of tumor necrosis factor-alpha correlates with grade of inflammation in untreated ulcerative colitis. Scand J Gastroenterol 42 : 1312–1320.

33. ComerfordI, MilastaS, MorrowV, MilliganG, NibbsR (2006) The chemokine receptor CCX-CKR mediates effective scavenging of CCL19 in vitro. Eur J Immunol 36 : 1904–1916.

34. GrahamGJ (2009) D6 and the atypical chemokine receptor family: novel regulators of immune and inflammatory processes. Eur J Immunol 39 : 342–351.

35. MeurensF, BerriM, AurayG, MeloS, LevastB, et al. (2009) Early immune response following Salmonella enterica subspecies enterica serovar Typhimurium infection in porcine jejunal gut loops. Vet Res 40 : 5.

36. PetreacaML, DoD, DhallS, McLellandD, SerafinoA, et al. (2012) Deletion of a tumor necrosis superfamily gene in mice leads to impaired healing that mimics chronic wounds in humans. Wound Repair Regen 20 : 353–366.

37. StanleyAC, de Labastida RiveraF, HaqueA, SheelM, ZhouY, et al. (2011) Critical roles for LIGHT and its receptors in generating T cell-mediated immunity during Leishmania donovani infection. PLoS Pathog 7: e1002279.

38. ChomontN, El-FarM, AncutaP, TrautmannL, ProcopioFA, et al. (2009) HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 15 : 893–900.

39. SandlerNG, WandH, RoqueA, LawM, NasonMC, et al. (2011) Plasma levels of soluble CD14 independently predict mortality in HIV infection. The Journal of infectious diseases 203 : 780–790.

40. HearpsAC, MaisaA, ChengWJ, AngelovichTA, LichtfussGF, et al. (2012) HIV infection induces age-related changes to monocytes and innate immune activation in young men that persist despite combination antiretroviral therapy. AIDS 26 : 843–853.

41. YoshidaH, RussellJ, SenchenkovaEY, Almeida PaulaLD, GrangerDN (2010) Interleukin-1beta mediates the extra-intestinal thrombosis associated with experimental colitis. Am J Pathol 177 : 2774–2781.

42. YoshidaH, YilmazCE, GrangerDN (2011) Role of tumor necrosis factor-alpha in the extraintestinal thrombosis associated with colonic inflammation. Inflamm Bowel Dis 17 : 2217–2223.

43. CicconeEJ, GreenwaldJH, LeePI, BiancottoA, ReadSW, et al. (2011) CD4+ T cells, including Th17 and cycling subsets, are intact in the gut mucosa of HIV-1-infected long-term nonprogressors. Journal of virology 85 : 5880–5888.

44. PalmerS, WiegandAP, MaldarelliF, BazmiH, MicanJM, et al. (2003) New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol 41 : 4531–4536.