Interferon-α Subtypes in an Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms

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The therapeutic potential of recombinant IFNα against HIV-1 infection has been explored for 25 years, but its effectiveness was inconsistent. However, these clinical trials administered IFNα2, which is only one member of a 12-protein family of IFNα subtypes. More recently, IFNα was found to activate ‘restriction factors’–proteins that can directly inhibit HIV-1. To date, it remains unknown which IFNα subtypes are produced by professional IFNα producing cells known as plasmacytoid dendritic cells and which IFNα subtypes are more effective in inhibiting HIV-1 infection in the gastrointestinal tract, the primary site of early HIV-1 replication. Here, we show that weaker IFNα subtypes were more highly expressed following HIV-1 infection. Using an infection platform that captures important characteristics of early HIV-1 infection in the gut, several IFNα subtypes were found to be more effective at inhibiting HIV-1 than IFNα2. In particular, IFNα8 and IFNα14 more potently reduced the infectivity of HIV-1 virions, an activity that can be attributed to the APOBEC3 proteins. Our findings strongly support the evaluation of potent IFNα subtypes in currently evolving HIV-1 curative strategies.

Vyšlo v časopise: Interferon-α Subtypes in an Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms. PLoS Pathog 11(11): e32767. doi:10.1371/journal.ppat.1005254
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005254

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1. Samarajiwa SA, Forster S, Auchettl K, Hertzog PJ (2009) INTERFEROME: the database of interferon regulated genes. Nucleic Acids Res 37: D852–857. doi: 10.1093/nar/gkn732 18996892

2. Pestka S (2007) The interferons: 50 years after their discovery, there is much more to learn. J Biol Chem 282: 20047–20051. 17502369

3. Lane HC, Kovacs JA, Feinberg J, Herpin B, Davey V, et al. (1988) Anti-retroviral effects of interferon-alpha in AIDS-associated Kaposi's sarcoma. Lancet 2: 1218–1222. 2903954

4. Hatzakis A, Gargalianos P, Kiosses V, Lazanas M, Sypsa V, et al. (2001) Low-dose IFN-alpha monotherapy in treatment-naive individuals with HIV-1 infection: evidence of potent suppression of viral replication. J Interferon Cytokine Res 21: 861–869. 11710999

5. Boue F, Reynes J, Rouzioux C, Emilie D, Souala F, et al. (2011) Alpha interferon administration during structured interruptions of combination antiretroviral therapy in patients with chronic HIV-1 infection: INTERVAC ANRS 105 trial. AIDS 25: 115–118. doi: 10.1097/QAD.0b013e328340a1e7 20962614

6. Asmuth DM, Murphy RL, Rosenkranz SL, Lertora JJ, Kottilil S, et al. (2011) Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon Alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial. J Infect Dis 201: 1686–1696.

7. Malim MH, Bieniasz PD (2012) HIV Restriction Factors and Mechanisms of Evasion. Cold Spring Harb Perspect Med 2: a006940. doi: 10.1101/cshperspect.a006940 22553496

8. Azzoni L, Foulkes AS, Papasavvas E, Mexas AM, Lynn KM, et al. (2013) Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J Infect Dis 207: 213–222. doi: 10.1093/infdis/jis663 23105144

9. Sun H, Buzon MJ, Shaw A, Berg RK, Yu XG, et al. (2014) Hepatitis C therapy with interferon-alpha and ribavirin reduces CD4 T-cell-associated HIV-1 DNA in HIV-1/hepatitis C virus-coinfected patients. J Infect Dis 209: 1315–1320. doi: 10.1093/infdis/jit628 24277743

10. Hoffmann HH, Schneider WM, Rice CM (2015) Interferons and viruses: an evolutionary arms race of molecular interactions. Trends Immunol 36: 124–138. doi: 10.1016/j.it.2015.01.004 25704559

11. Gibbert K, Schlaak JF, Yang D, Dittmer U (2013) IFN-alpha subtypes: distinct biological activities in anti-viral therapy. Br J Pharmacol 168: 1048–1058. doi: 10.1111/bph.12010 23072338

12. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, et al. (1999) The nature of the principal type 1 interferon-producing cells in human blood. Science 284: 1835–1837. 10364556

13. O'Brien M, Manches O, Sabado RL, Baranda SJ, Wang Y, et al. (2011) Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-alpha-producing and partially matured phenotype. J Clin Invest 121: 1088–1101. doi: 10.1172/JCI44960 21339641

14. Lepelley A, Louis S, Sourisseau M, Law HK, Pothlichet J, et al. (2011) Innate sensing of HIV-infected cells. PLoS Pathog 7: e1001284. doi: 10.1371/journal.ppat.1001284 21379343

15. Szubin R, Chang WL, Greasby T, Beckett L, Baumgarth N (2008) Rigid interferon-alpha subtype responses of human plasmacytoid dendritic cells. J Interferon Cytokine Res 28: 749–763. doi: 10.1089/jir.2008.0037 18937549

16. Honda K, Takaoka A, Taniguchi T (2006) Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 25: 349–360. 16979567

17. Easlick J, Szubin R, Lantz S, Baumgarth N, Abel K (2010) The early interferon alpha subtype response in infant macaques infected orally with SIV. J Acquir Immune Defic Syndr 55: 14–28. doi: 10.1097/QAI.0b013e3181e696ca 20616742

18. Meixlsperger S, Leung CS, Ramer PC, Pack M, Vanoaica LD, et al. (2013) CD141+ dendritic cells produce prominent amounts of IFN-alpha after dsRNA recognition and can be targeted via DEC-205 in humanized mice. Blood 121: 5034–5044. doi: 10.1182/blood-2012-12-473413 23482932

19. Hillyer P, Mane VP, Schramm LM, Puig M, Verthelyi D, et al. (2012) Expression profiles of human interferon-alpha and interferon-lambda subtypes are ligand- and cell-dependent. Immunol Cell Biol 90: 774–783. doi: 10.1038/icb.2011.109 22249201

20. Izaguirre A, Barnes BJ, Amrute S, Yeow WS, Megjugorac N, et al. (2003) Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells. J Leukoc Biol 74: 1125–1138. 12960254

21. Jaks E, Gavutis M, Uze G, Martal J, Piehler J (2007) Differential receptor subunit affinities of type I interferons govern differential signal activation. J Mol Biol 366: 525–539. 17174979

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

23. Cull VS, Tilbrook PA, Bartlett EJ, Brekalo NL, James CM (2003) Type I interferon differential therapy for erythroleukemia: specificity of STAT activation. Blood 101: 2727–2735. 12446459

24. Vazquez N, Schmeisser H, Dolan MA, Bekisz J, Zoon KC, et al. (2011) Structural variants of IFNalpha preferentially promote antiviral functions. Blood 118: 2567–2577. doi: 10.1182/blood-2010-12-325027 21757613

25. Gibbert K, Joedicke JJ, Meryk A, Trilling M, Francois S, et al. (2012) Interferon-alpha subtype 11 activates NK cells and enables control of retroviral infection. PLoS Pathog 8: e1002868. doi: 10.1371/journal.ppat.1002868 22912583

26. Sperber SJ, Gocke DJ, Haberzettl C, Kuk R, Schwartz B, et al. (1992) Anti-HIV-1 activity of recombinant and hybrid species of interferon-alpha. J Interferon Res 12: 363–368. 1331260

27. Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E, et al. (2009) 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 83: 3719–3733. doi: 10.1128/JVI.01844-08 19176632

28. Sandler NG, Bosinger SE, Estes JD, Zhu RT, Tharp GK, et al. (2014) Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature 511: 601–605. doi: 10.1038/nature13554 25043006

29. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, et al. (2004) CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 200: 749–759. 15365096

30. Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, et al. (2004) Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 200: 761–770. 15365095

31. Lapenta C, Boirivant M, Marini M, Santini SM, Logozzi M, et al. (1999) Human intestinal lamina propria lymphocytes are naturally permissive to HIV-1 infection. Eur J Immunol 29: 1202–1208. 10229087

32. Steele AK, Lee EJ, Manuzak JA, Dillon SM, Beckham JD, et al. (2014) Microbial exposure alters HIV-1-induced mucosal CD4+ T cell death pathways Ex vivo. Retrovirology 11: 14. doi: 10.1186/1742-4690-11-14 24495380

33. Dillon SM, Manuzak JA, Leone AK, Lee EJ, Rogers LM, et al. (2012) HIV-1 infection of human intestinal lamina propria CD4+ T cells in vitro is enhanced by exposure to commensal Escherichia coli. J Immunol 189: 885–896. doi: 10.4049/jimmunol.1200681 22689879

34. Kane M, Yadav SS, Bitzegeio J, Kutluay SB, Zang T, et al. (2013) MX2 is an interferon-induced inhibitor of HIV-1 infection. Nature 502: 563–566.

35. Goujon C, Moncorge O, Bauby H, Doyle T, Ward CC, et al. (2013) Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature 502: 559–562.

36. Van Damme N, Goff D, Katsura C, Jorgenson RL, Mitchell R, et al. (2008) The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe 3: 245–252. doi: 10.1016/j.chom.2008.03.001 18342597

37. Neil SJ, Zang T, Bieniasz PD (2008) Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451: 425–430. doi: 10.1038/nature06553 18200009

38. Pillai SK, Abdel-Mohsen M, Guatelli J, Skasko M, Monto A, et al. (2012) Role of retroviral restriction factors in the interferon-alpha-mediated suppression of HIV-1 in vivo. Proc Natl Acad Sci U S A 109: 3035–3040. doi: 10.1073/pnas.1111573109 22315404

39. Abdel-Mohsen M, Deng X, Liegler T, Guatelli JC, Salama MS, et al. (2014) Effects of alpha interferon treatment on intrinsic anti-HIV-1 immunity in vivo. J Virol 88: 763–767. doi: 10.1128/JVI.02687-13 24155399

40. Liu Z, Pan Q, Ding S, Qian J, Xu F, et al. (2013) The interferon-inducible MxB protein inhibits HIV-1 infection. Cell Host Microbe 14: 398–410.

41. Peng G, Lei KJ, Jin W, Greenwell-Wild T, Wahl SM (2006) Induction of APOBEC3 family proteins, a defensive maneuver underlying interferon-induced anti-HIV-1 activity. J Exp Med 203: 41–46. 16418394

42. Neil SJ, Sandrin V, Sundquist WI, Bieniasz PD (2007) An interferon-alpha-induced tethering mechanism inhibits HIV-1 and Ebola virus particle release but is counteracted by the HIV-1 Vpu protein. Cell Host Microbe 2: 193–203. 18005734

43. Bishop KN, Verma M, Kim EY, Wolinsky SM, Malim MH (2008) APOBEC3G inhibits elongation of HIV-1 reverse transcripts. PLoS Pathog 4: e1000231. doi: 10.1371/journal.ppat.1000231 19057663

44. Schumacher AJ, Hache G, Macduff DA, Brown WL, Harris RS (2008) The DNA deaminase activity of human APOBEC3G is required for Ty1, MusD, and human immunodeficiency virus type 1 restriction. J Virol 82: 2652–2660. doi: 10.1128/JVI.02391-07 18184715

45. Harper MS, Barrett BS, Smith DS, Li SX, Gibbert K, et al. (2013) IFN-alpha treatment inhibits acute Friend retrovirus replication primarily through the antiviral effector molecule Apobec3. J Immunol 190: 1583–1590. doi: 10.4049/jimmunol.1202920 23315078

46. Duggal NK, Emerman M (2012) Evolutionary conflicts between viruses and restriction factors shape immunity. Nat Rev Immunol 12: 687–695. doi: 10.1038/nri3295 22976433

47. Li H, Evans TI, Gillis J, Connole M, Reeves RK (2014) Bone Marrow-Imprinted Gut-Homing of Plasmacytoid Dendritic Cells (pDCs) in Acute Simian Immunodeficiency Virus Infection Results in Massive Accumulation of Hyperfunctional CD4+ pDCs in the Mucosae. J Infect Dis.

48. Lehmann C, Jung N, Forster K, Koch N, Leifeld L, et al. (2014) Longitudinal analysis of distribution and function of plasmacytoid dendritic cells in peripheral blood and gut mucosa of HIV infected patients. J Infect Dis 209: 940–949. doi: 10.1093/infdis/jit612 24259523

49. Dillon SM, Lee EJ, Kotter CV, Austin GL, Gianella S, et al. (2015) Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T-cell activation in untreated HIV-1 infection. Mucosal Immunol.

50. Dillon SM, Friedlander LJ, Rogers LM, Meditz AL, Folkvord JM, et al. (2011) Blood myeloid dendritic cells from HIV-1-infected individuals display a proapoptotic profile characterized by decreased Bcl-2 levels and by caspase-3+ frequencies that are associated with levels of plasma viremia and T cell activation in an exploratory study. J Virol 85: 397–409. doi: 10.1128/JVI.01118-10 20962079

51. Lindwasser OW, Chaudhuri R, Bonifacino JS (2007) Mechanisms of CD4 downregulation by the Nef and Vpu proteins of primate immunodeficiency viruses. Curr Mol Med 7: 171–184. 17346169

52. von Sydow M, Sonnerborg A, Gaines H, Strannegard O (1991) Interferon-alpha and tumor necrosis factor-alpha in serum of patients in various stages of HIV-1 infection. AIDS Res Hum Retroviruses 7: 375–380. 1906289

53. Shen R, Meng G, Ochsenbauer C, Clapham PR, Grams J, et al. (2011) Stromal down-regulation of macrophage CD4/CCR5 expression and NF-kappaB activation mediates HIV-1 non-permissiveness in intestinal macrophages. PLoS Pathog 7: e1002060. doi: 10.1371/journal.ppat.1002060 21637819

54. Sheehy AM, Gaddis NC, Choi JD, Malim MH (2002) Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418: 646–650. 12167863

55. Smith DS, Guo K, Barrett BS, Heilman KJ, Evans LH, et al. (2011) Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response. PLoS Pathog 7: e1002284. doi: 10.1371/journal.ppat.1002284 21998583

56. Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, et al. (2008) Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 105: 7552–7557. doi: 10.1073/pnas.0802203105 18490657

57. Parrish NF, Gao F, Li H, Giorgi EE, Barbian HJ, et al. (2013) Phenotypic properties of transmitted founder HIV-1. Proc Natl Acad Sci U S A 110: 6626–6633. doi: 10.1073/pnas.1304288110 23542380

58. Fenton-May AE, Dibben O, Emmerich T, Ding H, Pfafferott K, et al. (2013) Relative resistance of HIV-1 founder viruses to control by interferon-alpha. Retrovirology 10: 146. doi: 10.1186/1742-4690-10-146 24299076

59. Refsland EW, Hultquist JF, Harris RS (2012) Endogenous origins of HIV-1 G-to-A hypermutation and restriction in the nonpermissive T cell line CEM2n. PLoS Pathog 8: e1002800. doi: 10.1371/journal.ppat.1002800 22807680

60. Barrett BS, Guo K, Harper MS, Li SX, Heilman KJ, et al. (2014) Reassessment of murine APOBEC1 as a retrovirus restriction factor in vivo. Virology 468-470C: 601–608.

61. Yu Q, Konig R, Pillai S, Chiles K, Kearney M, et al. (2004) Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome. Nat Struct Mol Biol 11: 435–442. 15098018

62. Schreiber G, Piehler J (2015) The molecular basis for functional plasticity in type I interferon signaling. Trends Immunol 36: 139–149. doi: 10.1016/j.it.2015.01.002 25687684

63. Manry J, Laval G, Patin E, Fornarino S, Itan Y, et al. (2011) Evolutionary genetic dissection of human interferons. J Exp Med 208: 2747–2759. doi: 10.1084/jem.20111680 22162829

64. Foster GR, Rodrigues O, Ghouze F, Schulte-Frohlinde E, Testa D, et al. (1996) Different relative activities of human cell-derived interferon-alpha subtypes: IFN-alpha 8 has very high antiviral potency. J Interferon Cytokine Res 16: 1027–1033. 8974005

65. Moll HP, Maier T, Zommer A, Lavoie T, Brostjan C (2011) The differential activity of interferon-alpha subtypes is consistent among distinct target genes and cell types. Cytokine 53: 52–59. doi: 10.1016/j.cyto.2010.09.006 20943413

66. Yamamoto S, Yano H, Sanou O, Ikegami H, Kurimoto M, et al. (2002) Different antiviral activities of IFN-alpha subtypes in human liver cell lines: synergism between IFN-alpha2 and IFN-alpha8. Hepatol Res 24: 99. 12270738

67. Lehmann C, Taubert D, Jung N, Fatkenheuer G, van Lunzen J, et al. (2009) Preferential upregulation of interferon-alpha subtype 2 expression in HIV-1 patients. AIDS Res Hum Retroviruses 25: 577–581. doi: 10.1089/aid.2008.0238 19500019

68. Hardy GA, Sieg SF, Rodriguez B, Jiang W, Asaad R, et al. (2009) Desensitization to type I interferon in HIV-1 infection correlates with markers of immune activation and disease progression. Blood 113: 5497–5505. doi: 10.1182/blood-2008-11-190231 19299650

69. Ries M, Pritschet K, Schmidt B (2012) Blocking type I interferon production: a new therapeutic option to reduce the HIV-1-induced immune activation. Clin Dev Immunol 2012: 534929. doi: 10.1155/2012/534929 22203858

70. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, et al. (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472: 481–485. doi: 10.1038/nature09907 21478870

71. Stopak KS, Chiu YL, Kropp J, Grant RM, Greene WC (2007) Distinct patterns of cytokine regulation of APOBEC3G expression and activity in primary lymphocytes, macrophages, and dendritic cells. J Biol Chem 282: 3539–3546. 17110377

72. Refsland EW, Stenglein MD, Shindo K, Albin JS, Brown WL, et al. (2010) Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction. Nucleic Acids Res 38: 4274–4284. doi: 10.1093/nar/gkq174 20308164

73. Simon V, Zennou V, Murray D, Huang Y, Ho DD, et al. (2005) Natural variation in Vif: differential impact on APOBEC3G/3F and a potential role in HIV-1 diversification. PLoS Pathog 1: e6. 16201018

74. Santiago ML, Greene WC (2008) The role of the Apobec3 family of cytidine deaminases in innate immunity, G-to-A hypermutation and evolution of retroviruses. In: Domingo E, Parrish CR, Holland JJ, editors. Origin and Evolution of Viruses. London, UK: Academic Press. pp. 183–206.

75. Sadler HA, Stenglein MD, Harris RS, Mansky LM (2010) APOBEC3G contributes to HIV-1 variation through sublethal mutagenesis. J Virol 84: 7396–7404. doi: 10.1128/JVI.00056-10 20463080

76. Kim EY, Lorenzo-Redondo R, Little SJ, Chung YS, Phalora PK, et al. (2014) Human APOBEC3 Induced Mutation of Human Immunodeficiency Virus Type-1 Contributes to Adaptation and Evolution in Natural Infection. PLoS Pathog 10: e1004281. doi: 10.1371/journal.ppat.1004281 25080100

77. Wood N, Bhattacharya T, Keele BF, Giorgi E, Liu M, et al. (2009) HIV evolution in early infection: selection pressures, patterns of insertion and deletion, and the impact of APOBEC. PLoS Pathog 5: e1000414. doi: 10.1371/journal.ppat.1000414 19424423

78. Cavrois M, Neidleman J, Galloway N, Derdeyn CA, Hunter E, et al. (2011) Measuring HIV fusion mediated by envelopes from primary viral isolates. Methods 53: 34–38. doi: 10.1016/j.ymeth.2010.05.010 20554044

79. Halemano K, Guo K, Heilman KJ, Barrett BS, Smith DS, et al. (2014) Immunoglobulin somatic hypermutation by APOBEC3/Rfv3 during retroviral infection. Proc Natl Acad Sci U S A 111: 7759–7764. doi: 10.1073/pnas.1403361111 24821801