HIV infection does not alter interferon α/β receptor 2 expression on mucosal immune cells

Autoři: Julia Ickler aff001;  Sandra Francois aff001;  Marek Widera aff001;  Mario L. Santiago aff002;  Ulf Dittmer aff001;  Kathrin Sutter aff001
Působiště autorů: Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany aff001;  Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America aff002
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article


The innate immune response induced by type I interferons (IFNs) plays a critical role in the establishment of HIV infection. IFNs are induced early in HIV infection and trigger an antiviral defense program by signaling through the IFNα/β receptor (IFNAR), which consists of two subunits, IFNAR1 and IFNAR2. Changes in IFNAR expression in HIV target cells, as well as other immune cells, could therefore have important consequences for initial HIV spread. It was previously reported that IFNAR2 expression is increased in peripheral blood CD4+ CXCR4+ T cells of HIV+ patients compared to HIV uninfected controls, suggesting that HIV infection may alter the IFN responsiveness of target cells. However, the earliest immune cells affected by HIV in vivo reside in the gut-associated lymphoid tissue (GALT). To date, it remains unknown if IFNAR expression is altered in GALT immune cells in the context of HIV infection and exposure to IFNs, including the 12 IFNα subtypes. Here, we analyzed the expression of surface bound and soluble IFNAR2 on Lamina propria mononuclear cells (LPMCs) isolated from the GALT of HIV- individuals and in plasma samples of HIV+ patients. IFNAR2 expression varied between different T cells, B cells and natural killer cells, but was not altered following HIV infection. Furthermore, expression of the soluble IFNAR2a isoform was not changed in HIV+ patients compared to healthy donors, nor in LPMCs after HIV-1 infection ex vivo. Even though the 12 human IFNα subtypes trigger different biological responses and vary in their affinity to both receptor subunits, stimulation of LPMCs with different recombinant IFNα subtypes did not result in any significant changes in IFNAR2 surface expression. Our data suggests that potential changes in the IFN responsiveness of mucosal immune cells during HIV infection are unlikely dictated by changes in IFNAR2 expression.

Klíčová slova:

B cells – Cytotoxic T cells – HIV – HIV infections – Immune cells – Interferons – Messenger RNA – T cells


1. Brenchley JM, Douek DC. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 2008;1: 23–30. doi: 10.1038/mi.2007.1 19079157

2. Marchetti G, Tincati C, Silvestri G. Microbial Translocation in the Pathogenesis of HIV Infection and AIDS. Clin Microbiol Rev. 2013;23. doi: 10.1128/CMR.00050-12 23297256

3. Zevin AS, McKinnon L, Burgener A, Klatt NR. Microbial translocation and microbiome dysbiosis in HIV-associated immune activation. Curr Opin HIV AIDS. NIH Public Access; 2016;11: 182–90. doi: 10.1097/COH.0000000000000234 26679414

4. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, et al. CD4 + T Cell Depletion During All Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract. Pediatrics. 2017;116: 572.1–573. doi: 10.1542/peds.2005-0698bbbb

5. Schneider T, Jahn H, Schmidt W, Riecken E, Zeitz M, Ullrich R, et al. Loss of CD4 T lymphocytes in patients infected with human immunodeficiency virus type 1 is more pronounced in the duodenal mucosa than in the peripheral blood [Internet]. Gut. 1995. Available:

6. Belyakov IM, Ahlers JD. Functional CD8+ CTLs in mucosal sites and HIV infection: moving forward toward a mucosal AIDS vaccine. Trends Immunol. Elsevier Current Trends; 2008;29: 574–585. doi: 10.1016/J.IT.2008.07.010 18838298

7. Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J, Mcneil A, et al. 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. 2003;77: 11708–11717. doi: 10.1128/JVI.77.21.11708-11717.2003 14557656

8. Lapenta C, Boirivant M, Marini M, Santini SM, Logozzi M, Viora M, et al. Human intestinal lamina propria lymphocytes are naturally permissive to HIV-1 infection. Eur J Immunol. 1999;29: 1202–1208. doi: 10.1002/(SICI)1521-4141(199904)29:04<1202::AID-IMMU1202>3.0.CO;2-O 10229087

9. Harper MS, Guo K, Gibbert K, Lee EJ, Dillon SM, Barrett BS, et al. Interferon-α Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms. PLOS Pathog. 2015;11: e1005254. doi: 10.1371/journal.ppat.1005254 26529416

10. Weissmann C, Weber H. The interferon genes. Prog Nucleic Acid Res Mol Biol. 1986;33: 251–300. Available: doi: 10.1016/s0079-6603(08)60026-4

11. Hardy MP, Owczarek CM, Jermiin LS, Ejdebäck M, Hertzog PJ. Characterization of the type I interferon locus and identification of novel genes. Genomics. 2004;84: 331–345. doi: 10.1016/j.ygeno.2004.03.003 15233997

12. De Weerd NA, Nguyen T. The interferons and their receptors-distribution and regulation. Immunol Cell Biol. Nature Publishing Group; 2012;90: 483–491. doi: 10.1038/icb.2012.9 22410872

13. Sutter K, Dickow J, Dittmer U. Interferon α subtypes in HIV infection. Cytokine Growth Factor Rev. Elsevier; 2018;40: 13–18. doi: 10.1016/j.cytogfr.2018.02.002 29475588

14. Gazziola C, Cordani N, Carta S, De Lorenzo E, Colombatti A, Perris R. The relative endogenous expression levels of the IFNAR2 isoforms influence the cytostatic and pro-apoptotic effect of IFNα on pleomorphic sarcoma cells. Int J Oncol. Spandidos Publications; 2005;26: 129–140. doi: 10.3892/ijo.26.1.129

15. Hardy MP, Owczarek CM, Trajanovska S, Liu X, Kola I, Hertzog PJ. The soluble murine type I interferon receptor Ifnar-2 is present in serum, is independently regulated, and has both agonistic and antagonistic properties. Blood. 2001;97: 473–482. doi: 10.1182/blood.v97.2.473 11154225

16. Chadha K, Weinstock-Guttman B, Zivadinov R, Bhasi K, Muhitch J, Feichter J, et al. Interferon Inhibitory Activity in Patients With Multiple Sclerosis. Arch Neurol. 2006;63: 1579. doi: 10.1001/archneur.63.11.1579 17101826

17. Ambrus JLS, Dembinski W, Ambrus JLJ, Sykes DE, Akhter S, Kulaylat MN, et al. Free interferon-?/? receptors in the circulation of patients with adenocarcinoma. Cancer. 2003;98: 2730–2733. doi: 10.1002/cncr.11843 14669296

18. Tanaka S, Hattori N, Ishikawa N, Horimasu Y, Deguchi N, Takano A, et al. Interferon (alpha, beta and omega) receptor 2 is a prognostic biomarker for lung cancer. Pathobiology. 2012;79: 24–33. doi: 10.1159/000331230 22236545

19. Mizukoshi E, Kaneko S, Kaji K, Terasaki S, Matsushita E, Muraguchi M, et al. Serum Levels of Soluble Interferon Alfa / Beta Receptor as an Inhibitory Factor of Interferon in the Patients With Chronic Hepatitis C. Hepatology. 1999;30: 1325–1331. doi: 10.1002/hep.510300516 10534358

20. Li Y, Sun B, Esser S, Jessen H, Streeck H, Widera M, et al. Expression Pattern of Individual IFNA Subtypes in Chronic HIV Infection. J Interf Cytokine Res. 2017;37: 541–549. doi: 10.1089/jir.2017.0076 29252127

21. Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E, Heitman J, et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol. American Society for Microbiology (ASM); 2009;83: 3719–33. doi: 10.1128/JVI.01844-08 19176632

22. von SYDOW M, SÖNNERBORG A, GAINES H, STRANNEGÅRD Ö. Interferon-Alpha and Tumor Necrosis Factor-Alpha in Serum of Patients in Various Stages of HIV-1 Infection. AIDS Res Hum Retroviruses. 1991;7: 375–380. doi: 10.1089/aid.1991.7.375 1906289

23. Cheng L, Yu H, Li G, Li F, Ma J, Li J, et al. Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection. JCI Insight. 2017;2. doi: 10.1172/jci.insight.94366 28614789

24. Utay NS, Douek DC. Interferons and HIV Infection: The Good, the Bad, and the Ugly. Pathog Immun. 2016;1: 107. doi: 10.20411/pai.v1i1.125 27500281

25. Kwaa AKR, Talana CAG, Blankson JN. Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+ T Cells. 2019; doi: 10.1128/JVI.01541-18 30404799

26. Cheng L, Ma J, Li J, Li D, Li G, Li F, et al. Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs. J Clin Invest. 2017;127: 269–279. doi: 10.1172/JCI90745 27941247

27. Alston B, Ellenberg JH, Standiford HC, Muth K, Martinez A, Greaves W, et al. A multicenter, randomized, controlled trial of three preparations of low-dose oral alpha-interferon in HIV-infected patients with CD4+ counts between 50 and 350 cells/mm(3). Division of AIDS Treatment Research Initiative (DATRI) 022 Study Group. J Acquir Immune Defic Syndr. 1999;22: 348–57. Available: doi: 10.1097/00126334-199912010-00005

28. Bosinger SE, Utay NS. Type I Interferon: Understanding Its Role in HIV Pathogenesis and Therapy. Curr HIV/AIDS Rep. Springer US; 2015;12: 41–53. doi: 10.1007/s11904-014-0244-6 25662992

29. Katabira ET, Sewankambo NK, Mugerwa RD, Belsey EM, Mubiru FX, Othieno C, et al. Lack of eYcacy of low dose oral interferon alfa in symptomatic HIV-1 infection: a randomised, double blind, placebo controlled trial [Internet]. Available:

30. Doyle T, Goujon C, Malim MH. HIV-1 and interferons: Who’s interfering with whom? Nat Rev Microbiol. Nature Publishing Group; 2015;13: 403–413. doi: 10.1038/nrmicro3449 25915633

31. Lavender KJ, Gibbert K, Peterson KE, Van Dis E, Verheyen J, Müller JA, et al. Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo. J Virol. 2016;90: 6001–6013. doi: 10.1128/JVI.00451-16 27099312

32. Abraham S, Choi J-G, Ortega NM, Zhang J, Shankar P, Swamy NM. Gene therapy with plasmids encoding IFN-β or IFN-α14 confers long-term resistance to HIV-1 in humanized mice. Oncotarget. Impact Journals, LLC; 2016;7: 78412–78420. doi: 10.18632/oncotarget.12512 27729616

33. Sutter K, Lavender KJ, Messer RJ, Widera M, Williams K, Race B, et al. Concurrent administration of IFNα14 and cART in TKO-BLT mice enhances suppression of HIV-1 viremia but does not eliminate the latent reservoir. Sci Rep. Nature Research; 2019;9. doi: 10.1038/s41598-019-54650-9 31792317

34. Yoder AC, Guo K, Dillon SM, Phang T, Lee EJ, Harper MS, et al. The transcriptome of HIV-1 infected intestinal CD4+ T cells exposed to enteric bacteria. Desrosiers RC, editor. PLOS Pathog. Public Library of Science; 2017;13: e1006226. doi: 10.1371/journal.ppat.1006226 28241075

35. Killian MS, Fujimura SH, Sudhagoni RG. Increased expression of the Type i interferon receptor on CD4 + T lymphocytes in HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2017;74: 473–478. doi: 10.1097/QAI.0000000000001280 28009639

36. Howe R, Dillon S, Rogers L, Mccarter M, Kelly C, Madinger N, et al. Evidence for Dendritic Cell-Dependent CD4+ T Helper-1 Type Responses to Commensal Bacteria in Normal Human Intestinal Lamina Propria. Clini Immunol. 2010;131: 317–332. doi: 10.1016/j.clim.2008.12.003.Evidence

37. Münch J, Rajan D, Schindler M, Specht A, Rücker E, Novembre FJ, et al. Nef-Mediated Enhancement of Virion Infectivity and Stimulation of Viral Replication Are Fundamental Properties of Primate Lentiviruses. J Virol. 2007;81: 13852–13864. doi: 10.1128/JVI.00904-07 17928336

38. Papkalla A, Münch J, Otto C, Kirchhoff F. NOTES Nef Enhances Human Immunodeficiency Virus Type 1 Infectivity and Replication Independently of Viral Coreceptor Tropism. J Virol. 2002;76: 8455–8459. doi: 10.1128/JVI.76.16.8455-8459.2002 12134048

39. Bauer A, Rudzki D, Auer M, Hegen H, Deisenhammer F. Expression of interferon type-I receptor isoforms, clinical response and development of neutralizing antibodies in multiple sclerosis patients–results of a prospective study. LaboratoriumsMedizin. De Gruyter; 2016;40: 119–124. doi: 10.1515/labmed-2015-0020

40. Farmer JR, Altschaefl KM, O’Shea KS, Miller DJ. Activation of the Type I Interferon Pathway Is Enhanced in Response to Human Neuronal Differentiation. Vasilakis N, editor. PLoS One. Public Library of Science; 2013;8: e58813. doi: 10.1371/journal.pone.0058813 23505563

41. Marijanovic Z, Ragimbeau J, van der Heyden J, Uzé G, Pellegrini S. Comparable potency of IFNalpha2 and IFNbeta on immediate JAK/STAT activation but differential down-regulation of IFNAR2. Biochem J. Portland Press Ltd; 2007;407: 141–51. doi: 10.1042/BJ20070605 17627610

42. Killian MS, Fujimura SH, Sudhagoni RG. Increased expression of the Type i interferon receptor on CD4+T lymphocytes in HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2017;74: 473–478. doi: 10.1097/QAI.0000000000001280 28009639

43. Tochizawa S, Akamatsu S, Sugiyama Y, Muraguchi M, Ohmoto Y, Ono Y, et al. A flow cytometric method for determination of the interferon receptor IFNAR2 subunit in peripheral blood leukocyte subsets. J Pharmacol Toxicol Methods. Elsevier; 2004;50: 59–66. doi: 10.1016/J.VASCN.2004.02.003 15233969

44. Tomasello E, Pollet E, Vu Manh TP, Uzé G, Dalod M. Harnessing mechanistic knowledge on beneficial versus deleterious IFN-I effects to design innovative immunotherapies targeting cytokine activity to specific cell types. Front Immunol. 2014;5: 1–27. doi: 10.3389/fimmu.2014.00001 24474949

45. Xia C, Vijayan M, Pritzl CJ, Fuchs SY, McDermott AB, Hahm B. Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1. J Virol. 2016;90: 2403–2417. doi: 10.1128/JVI.02749-15 26676772

46. Jia D, Rahbar R, Chan RWY, Lee SMY, Chan MCW, Wang BX, et al. Influenza virus non-structural protein 1 (NS1) disrupts interferon signaling. PLoS One. 2010;5. doi: 10.1371/journal.pone.0013927 21085662

47. Samarajiwa SA, Mangan NE, Hardy MP, Najdovska M, Dubach D, Braniff S-J, et al. TLR4-Mediated Septic Shock Type I IFN Signaling and Exacerbates Soluble IFN Receptor Potentiates In Vivo. 2014;.

48. Fatakdawala T, Skawinski M, Ferriera J, Stauffer T, Lavoie T. Soluble Type I Interferon Receptor 2 Is Elevated By Interferon Treatment and In Certain Autoimmune Diseases—ACR Meeting Abstracts [Internet]. 2013 [cited 2 Jun 2019]. Available:

49. Órpez-Zafra T, Pavía J, Hurtado-Guerrero I, Pinto-Medel MJ, Rodriguez Bada JL, Urbaneja P, et al. Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker. Mult Scler J. SAGE PublicationsSage UK: London, England; 2017;23: 937–945. doi: 10.1177/1352458516667564 27613121

50. Abudulai L, CHa L, Fernandez S, French M. INCREASED INTERFERON-ALPHA ACTIVITY MAY CONTRIBUTE TO DEFECTS OF B CELLS AND ANTIBODY PRODUCTION CAUSED BY HIV-1 INFECTION. In: Jornal of Virus Eradication, Abstratcs of the IAS 2016 Towards and HIV Cure Symposium [Internet]. 2016 [cited 2 Jun 2019].

51. Fuchs SY. Hope and Fear for Interferon: The Receptor-Centric Outlook on the Future of Interferon Therapy. J Interf Cytokine Res. Mary Ann Liebert, Inc.; 2013;33: 211. doi: 10.1089/JIR.2012.0117 23570388

52. Lavoie TB, Kalie E, Crisafulli-Cabatu S, Abramovich R, DiGioia G, Moolchan K, et al. Binding and activity of all human alpha interferon subtypes. Cytokine. Elsevier Ltd; 2011;56: 282–289. doi: 10.1016/j.cyto.2011.07.019 21856167

53. Jaks E, Gavutis M, Uzé G, Martal J, Piehler J. Differential Receptor Subunit Affinities of Type I Interferons Govern Differential Signal Activation. J Mol Biol. 2007;366: 525–539. doi: 10.1016/j.jmb.2006.11.053 17174979

54. Katlinski K V., Gui J, Katlinskaya Y V., Ortiz A, Chakraborty R, Bhattacharya S, et al. Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment. Cancer Cell. 2017; doi: 10.1016/j.ccell.2017.01.004 28196594

55. Ragimbeau J, Dondi E, Alcover A, Eid P, Uzé G, Pellegrini S. The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression. EMBO J. 2003;22: 537–547. doi: 10.1093/emboj/cdg038 12554654

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