Simultaneous RNA quantification of human and retroviral genomes reveals intact interferon signaling in HTLV-1-infected CD4+ T cell lines

Virology Journal

Johan Van Weyenbergh⁸  Anne-Mieke Vandamme⁹  Bernardo Galvão-Castro⁴  Lourdes Farré⁵  Achiléa Bittencourt⁶  Ricardo Khouri⁵  Eduardo Gotuzzo¹  Michael Talledo²  Giovanni López²  Christophe Pannecouque⁷  Britta Moens³ 

[1] Departamento de Medicina, Facultad de Medicina, Universidad Peruana Cayetano Heredia, Lima, Peru;Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, 31, Peru;Laboratory of Clinical and Epidemiological Virology, Rega Institute for Medical Research, K.U.Leuven, Leuven, Belgium;Bahia School of Medicine and Public Health, Salvador-Bahia, Brazil;Gonçalo Moniz Research Center, Oswaldo Cruz Foundation (FIOCRUZ), Salvador-Bahia, Brazil;Department of Pathology, Professor Edgar Santos Teaching Hospital, Federal University of Bahia, Salvador-Bahia, Brazil;Laboratory for Virology and Chemotherapy, Rega Institute for Medical Research, K.U.Leuven, Leuven, Belgium;Institute for Immunological Investigation iii-INCT, Sao Paulo, Brazil;Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, Portugal

关键词: Antiviral activity;    IFN-α signaling;    HTLV-1;    HIV-1;    IFN-α;    Retrovirus;   

Others  :  1154054
DOI  :  10.1186/1743-422X-9-171

 received in 2012-03-01, accepted in 2012-08-17,  发布年份 2012

【 摘 要 】

Background

IFN-α contributes extensively to host immune response upon viral infection through antiviral, pro-apoptotic, antiproliferative and immunomodulatory activities. Although extensively documented in various types of human cancers and viral infections, controversy exists in the exact mechanism of action of IFN-α in human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1) retroviral infections.

Results

IFN-α displayed strong anti-HIV-1 effects in HIV-1/HTLV-1 co-infected MT-4 cells in vitro, demonstrated by the dose-dependent inhibition of the HIV-1-induced cytopathic effect (IC₅₀ = 83.5 IU/ml, p < 0.0001) and p24 levels in cell-free supernatant (IC₅₀ = 1.2 IU/ml, p < 0.0001). In contrast, IFN-α treatment did not affect cell viability or HTLV-1 viral mRNA levels in HTLV-1 mono-infected cell lines, based on flow cytometry and nCounter analysis, respectively. However, we were able to confirm the previously described post-transcriptional inhibition of HTLV-1 p19 secretion by IFN-α in cell lines (p = 0.0045), and extend this finding to primary Adult T cell Leukemia patient samples (p = 0.031). In addition, through microarray and nCounter analysis, we performed the first genome-wide simultaneous quantification of complete human and retroviral transciptomes, demonstrating significant transcriptional activation of interferon-stimulated genes without concomitant decrease of HTLV-1 mRNA levels.

Conclusions

Taken together, our results indicate that both the absence of in vitro antiproliferative and pro-apoptotic activity as well as the modest post-transcriptional antiviral activity of IFN-α against HTLV-1, were not due to a cell-intrinsic defect in IFN-α signalisation, but rather represents a retrovirus-specific phenomenon, considering the strong HIV-1 inhibition in co-infected cells.

【 授权许可】

   
2012 Moens et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Verdonck K, Gonzalez E, Van Dooren S, Vandamme AM, Vanham G, Gotuzzo E: Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis 2007, 7(4):266-281.
• [2]Kallings LO: The first postmodern pandemic: 25 years of HIV/AIDS. J Intern Med 2008, 263(3):218-243.
• [3]De Clercq E: Antiretroviral drugs. Curr Opin Pharmacol 2010, 10(5):507-515.
• [4]Gessain A, Barin F, Vernant JC, Gout O, Maurs L, Calender A, de The G: Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 1985, 2(8452):407-410.
• [5]Tajima K, Cartier L: Epidemiological features of HTLV-I and adult T cell leukemia. Intervirology 1995, 38(3–4):238-246.
• [6]Tsukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W: O'Mahony D, Janik JE, Bittencourt AL, Taylor GP, Yamaguchi K, Utsunomiya A, Tobinai K, Watanabe T: Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. J Clin Oncol 2009, 27(3):453-459.
• [7]Bazarbachi A, Plumelle Y, Carlos Ramos J, Tortevoye P, Otrock Z, Taylor G, Gessain A, Harrington W, Panelatti G, Hermine O: Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol 2010, 28(27):4177-4183.
• [8]Osame M, Usuku K, Izumo S, Ijichi N, Amitani H, Igata A, Matsumoto M, Tara M: HTLV-I associated myelopathy, a new clinical entity. Lancet 1986, 1(8488):1031-1032.
• [9]Izumo S, Umehara F, Osame M: HTLV-I-associated myelopathy. Neuropathology 2000, 20(Suppl):S65-S68.
• [10]Nakagawa M, Nakahara K, Maruyama Y, Kawabata M, Higuchi I, Kubota H, Izumo S, Arimura K, Osame M: Therapeutic trials in 200 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. J Neurovirol 1996, 2(5):345-355.
• [11]Vallinoto AC, Santana BB, dos Santos EL, Santo RR, Hermes RB, Sousa RC, Cayres-Vallinoto I, Machado LF, Ishak MO, Ishak R: FAS-670A/G single nucleotide polymorphism may be associated with human T lymphotropic virus-1 infection and clinical evolution to TSP/HAM. Virus Res 2012, 163(1):178-182.
• [12]Farre L, Bittencourt AL, Silva-Santos G, Almeida A, Silva AC, Decanine D, Soares GM, Alcantara LC, Van Dooren S, Galvão-Castro B, Vandamme AM, Van Weyenbergh J: Fas 670 promoter polymorphism is associated to susceptibility, clinical presentation, and survival in adult T cell leukemia. J Leukoc Biol 2008, 83(1):220-222.
• [13]Lane HC, Davey V, Kovacs JA, Feinberg J, Metcalf JA, Herpin B, Walker R, Deyton L, Davey RT, Falloon J, et al.: Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection. A randomized, placebo-controlled trial. Ann Intern Med 1990, 112(11):805-811.
• [14]Isaacs A, Lindenmann J: Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci 1957, 147(927):258-267.
• [15]Takaoka A, Yanai H: Interferon signalling network in innate defence. Cell Microbiol 2006, 8(6):907-922.
• [16]Platanias LC: Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 2005, 5(5):375-386.
• [17]Taniguchi T, Takaoka A: The interferon-alpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Curr Opin Immunol 2002, 14(1):111-116.
• [18]Trinchieri G: Type I interferon: friend or foe? J Exp Med 2010, 207(10):2053-2063.
• [19]de Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, Silverman RH, Williams BR: Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol 2001, 69(6):912-920.
• [20]Goujon C, Malim MH: Characterization of the alpha interferon-induced postentry block to HIV-1 infection in primary human macrophages and T cells. J Virol 2010, 84(18):9254-9266.
• [21]Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM, Foster GR, Stark GR: Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov 2007, 6(12):975-990.
• [22]King JK, Yeh SH, Lin MW, Liu CJ, Lai MY, Kao JH, Chen DS, Chen PJ: Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients: A pilot study. Hepatology 2002, 36(6):1416-1424.
• [23]Pflugheber J, Fredericksen B, Sumpter R, Wang C, Ware F, Sodora DL, Gale M: Regulation of PKR and IRF-1 during hepatitis C virus RNA replication. Proc Natl Acad Sci USA 2002, 99(7):4650-4655.
• [24]Golomb HM: Hairy cell leukemia: treatment successes in the past 25 years. J Clin Oncol 2008, 26(16):2607-2609.
• [25]Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002, 347(13):975-982.
• [26]Ferrantini M, Capone I, Belardelli F: Interferon-alpha and cancer: mechanisms of action and new perspectives of clinical use. Biochimie 2007, 89(6–7):884-893.
• [27]Moschos S, Kirkwood JM: Present role and future potential of type I interferons in adjuvant therapy of high-risk operable melanoma. Cytokine Growth Factor Rev 2007, 18(5–6):451-458.
• [28]van Boxel-Dezaire AH, Rani MR, Stark GR: Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 2006, 25(3):361-372.
• [29]Chevaliez S, Pawlotsky JM: Interferon-based therapy of hepatitis C. Adv Drug Deliv Rev 2007, 59(12):1222-1241.
• [30]Pestka S, Krause CD, Walter MR: Interferons, interferon-like cytokines, and their receptors. Immunol Rev 2004, 202:8-32.
• [31]Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM: A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 2011, 472(7344):481-485.
• [32]Korth MJ, Taylor MD, Katze MG: Interferon inhibits the replication of HIV-1, SIV, and SHIV chimeric viruses by distinct mechanisms. Virology 1998, 247(2):265-273.
• [33]Hartshorn KL, Neumeyer D, Vogt MW, Schooley RT, Hirsch MS: Activity of interferons alpha, beta, and gamma against human immunodeficiency virus replication in vitro. AIDS Res Hum Retroviruses 1987, 3(2):125-133.
• [34]Okumura A, Lu G, Pitha-Rowe I, Pitha PM: Innate antiviral response targets HIV-1 release by the induction of ubiquitin-like protein ISG15. Proc Natl Acad Sci USA 2006, 103(5):1440-1445.
• [35]Agy MB, Acker RL, Sherbert CH, Katze MG: Interferon treatment inhibits virus replication in HIV-1- and SIV-infected CD4+ T-cell lines by distinct mechanisms: evidence for decreased stability and aberrant processing of HIV-1 proteins. Virology 1995, 214(2):379-386.
• [36]Baca-Regen L, Heinzinger N, Stevenson M, Gendelman HE: Alpha interferon-induced antiretroviral activities: restriction of viral nucleic acid synthesis and progeny virion production in human immunodeficiency virus type 1-infected monocytes. J Virol 1994, 68(11):7559-7565.
• [37]Coccia EM, Krust B, Hovanessian AG: Specific inhibition of viral protein synthesis in HIV-infected cells in response to interferon treatment. J Biol Chem 1994, 269(37):23087-23094.
• [38]Yamamoto JK, Barre-Sinoussi F, Bolton V, Pedersen NC, Gardner MB: Human alpha- and beta-interferon but not gamma- suppress the in vitro replication of LAV, HTLV-III, and ARV-2. J Interferon Res 1986, 6(2):143-152.
• [39]Mandl JN, Barry AP, Vanderford TH, Kozyr N, Chavan R, Klucking S, Barrat FJ, Coffman RL, Staprans SI, Feinberg MB: Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med 2008, 14(10):1077-1087.
• [40]Rotger M, Dang KK, Fellay J, Heinzen EL, Feng S, Descombes P, Shianna KV, Ge D, Gunthard HF, Goldstein DB, Telenti A: Genome-wide mRNA expression correlates of viral control in CD4+ T-cells from HIV-1-infected individuals. PLoS Pathog 2010, 6(2):e1000781.
• [41]von Sydow M, Sonnerborg A, Gaines H, Strannegard O: Interferon-alpha and tumor necrosis factor-alpha in serum of patients in various stages of HIV-1 infection. AIDS Res Hum Retroviruses 1991, 7(4):375-380.
• [42]Gringeri A, Musicco M, Hermans P, Bentwich Z, Cusini M, Bergamasco A, Santagostino E, Burny A, Bizzini B, Zagury D: Active anti-interferon-alpha immunization: a European-Israeli, randomized, double-blind, placebo-controlled clinical trial in 242 HIV-1–infected patients (the EURIS study). J Acquir Immune Defic Syndr Hum Retrovirol 1999, 20(4):358-370.
• [43]Herbeuval JP, Shearer GM: HIV-1 immunopathogenesis: how good interferon turns bad. Clin Immunol 2007, 123(2):121-128.
• [44]Haas DW, Lavelle J, Nadler JP, Greenberg SB, Frame P, Mustafa N, St Clair M, McKinnis R, Dix L, Elkins M, Rooney J: A randomized trial of interferon alpha therapy for HIV type 1 infection. AIDS Res Hum Retroviruses 2000, 16(3):183-190.
• [45]Asmuth DM, Murphy RL, Rosenkranz SL, Lertora JJ, Kottilil S, Cramer Y, Chan ES, Schooley RT, Rinaldo CR, Thielman N, Li XD, Wahl SM, Shore J, Janik J, Lempicki RA, Simpson Y, Pollard RB: 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 2010, 201(11):1686-1696.
• [46]Hatzakis A, Gargalianos P, Kiosses V, Lazanas M, Sypsa V, Anastassopoulou C, Vigklis V, Sambatakou H, Botsi C, Paraskevis D, Stalgis C: Low-dose IFN-alpha monotherapy in treatment-naive individuals with HIV-1 infection: evidence of potent suppression of viral replication. J Interferon Cytokine Res 2001, 21(10):861-869.
• [47]Feng X, Heyden NV, Ratner L: Alpha interferon inhibits human T-cell leukemia virus type 1 assembly by preventing Gag interaction with rafts. J Virol 2003, 77(24):13389-13395.
• [48]Feng X, Ratner L: Human T-cell leukemia virus type 1 blunts signaling by interferon alpha. Virology 2008, 374(1):210-216.
• [49]Zhang J, Yamada O, Kawagishi K, Araki H, Yamaoka S, Hattori T, Shimotohno K: Human T-cell leukemia virus type 1 Tax modulates interferon-alpha signal transduction through competitive usage of the coactivator CBP/p300. Virology 2008, 379(2):306-313.
• [50]Oliere S, Hernandez E, Lezin A, Arguello M, Douville R, Nguyen TL, Olindo S, Panelatti G, Kazanji M, Wilkinson P, Sekaly RP, Cesaire R, Hiscott J: HTLV-1 evades type I interferon antiviral signaling by inducing the suppressor of cytokine signaling 1 (SOCS1). PLoS Pathog 2010, 6(11):e1001177.
• [51]Gill PS, Harrington W, Kaplan MH, Ribeiro RC, Bennett JM, Liebman HA, Bernstein-Singer M, Espina BM, Cabral L, Allen S, et al.: Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med 1995, 332(26):1744-1748.
• [52]Izumo S, Goto I, Itoyama Y, Okajima T, Watanabe S, Kuroda Y, Araki S, Mori M, Nagataki S, Matsukura S, Akamine T, Nakagawa M, Yamamoto I, Osame M: Interferon-alpha is effective in HTLV-I-associated myelopathy: a multicenter, randomized, double-blind, controlled trial. Neurology 1996, 46(4):1016-1021.
• [53]Pannecouque C, Daelemans D, De Clercq E: Tetrazolium-based colorimetric assay for the detection of HIV replication inhibitors: revisited 20 years later. Nat Protoc 2008, 3(3):427-434.
• [54]Moens B, Decanine D, Menezes SM, Khouri R, Silva-Santos G, Lopez G, Alvarez C, Talledo M, Gotuzzo E, de Almeida Kruschewsky R, Galvão-Castro B, Vandamme AM, Van Weyenbergh J: Ascorbic Acid Has Superior Ex Vivo Antiproliferative, Cell Death-Inducing and Immunomodulatory Effects over IFN-α in HTLV-1-Associated Myelopathy. PLoS Negl Trop Dis 2012, 6(7):e1729.
• [55]Tattermusch S, Skinner JA, Chaussabel D, Banchereau J, Berry MP, McNab FW, O'Garra A, Taylor GP, Bangham CR: Systems Biology Approaches Reveal a Specific Interferon-Inducible Signature in HTLV-1 Associated Myelopathy. PLoS Pathog 2012, 8(1):e1002480.
• [56]Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, Fell HP, Ferree S, George RD, Grogan T, James JJ, Maysuria M, Mitton JD, Oliveri P, Osborn JL, Peng T, Ratcliffe AL, Webster PJ, Davidson EH, Hood L, Dimitrov K: Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol 2008, 26(3):317-325.
• [57]Chakrabarti A, Jha BK, Silverman RH: New insights into the role of RNase L in innate immunity. J Interferon Cytokine Res 2011, 31(1):49-57.
• [58]Charoenthongtrakul S, Zhou Q, Shembade N, Harhaj NS, Harhaj EW: Human T cell leukemia virus type 1 Tax inhibits innate antiviral signaling via NF-kappaB-dependent induction of SOCS1. J Virol 2011, 85(14):6955-6962.
• [59]Sharma S, Grandvaux N, Mamane Y, Genin P, Azimi N, Waldmann T, Hiscott J: Regulation of IFN regulatory factor 4 expression in human T cell leukemia virus-I-transformed T cells. J Immunol 2002, 169(6):3120-3130.
• [60]Imaizumi Y, Kohno T, Yamada Y, Ikeda S, Tanaka Y, Tomonaga M, Matsuyama T: Possible involvement of interferon regulatory factor 4 (IRF4) in a clinical subtype of adult T-cell leukemia. Jpn J Cancer Res 2001, 92(12):1284-1292.
• [61]Ramos JC, Ruiz P, Ratner L, Reis IM, Brites C, Pedroso C, Byrne GE, Toomey NL, Andela V, Harhaj EW, Lossos IS, Harrington WJ: IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. Blood 2007, 109(7):3060-3068.
• [62]Platanias LC: The p38 mitogen-activated protein kinase pathway and its role in interferon signaling. Pharmacol Ther 2003, 98(2):129-142.
• [63]Pedroso C, Netto EM, Weyll N, Brites C: Coinfection by HIV-1 and human lymphotropic virus type 1 in Brazilian children is strongly associated with a shorter survival time. J Acquir Immune Defic Syndr 2011, 57(Suppl 3):S208-S211.
• [64]Schechter M, Harrison LH, Halsey NA, Trade G, Santino M, Moulton LH, Quinn TC: Coinfection with human T-cell lymphotropic virus type I and HIV in Brazil. Impact on markers of HIV disease progression. JAMA 1994, 271(5):353-357.
• [65]Brites C, Sampalo J, Oliveira A: HIV/human T-cell lymphotropic virus coinfection revisited: impact on AIDS progression. AIDS Rev 2009, 11(1):8-16.
• [66]Van Weyenbergh J, Lipinski P, Abadie A, Chabas D, Blank U, Liblau R, Wietzerbin J: Antagonistic action of IFN-beta and IFN-gamma on high affinity Fc gamma receptor expression in healthy controls and multiple sclerosis patients. J Immunol 1998, 161(3):1568-1574.
• [67]Carneiro-Proietti AB, Catalan-Soares BC, Castro-Costa CM, Murphy EL, Sabino EC, Hisada M, Galvao-Castro B, Alcantara LC, Remondegui C, Verdonck K, Proietti FA: HTLV in the Americas: challenges and perspectives. Rev Panam Salud Publica 2006, 19(1):44-53.
• [68]Miyoshi I, Yoshimoto S, Kubonishi I, Taguchi H, Shiraishi Y, Ohtsuki Y, Akagi T: Transformation of normal human cord lymphocytes by co-cultivation with a lethally irradiated human T-cell line carrying type C virus particles. Gann 1981, 72(6):997-998.
• [69]Salahuddin SZ, Markham PD, Wong-Staal F, Franchini G, Kalyanaraman VS, Gallo RC: Restricted expression of human T-cell leukemia–lymphoma virus (HTLV) in transformed human umbilical cord blood lymphocytes. Virology 1983, 129(1):51-64.
• [70]Miyoshi I, Kubonishi I, Yoshimoto S, Shiraishi Y: A T-cell line derived from normal human cord leukocytes by co-culturing with human leukemic T-cells. Gann 1981, 72(6):978-981.
• [71]Harada S, Koyanagi Y, Yamamoto N: Infection of HTLV-III/LAV in HTLV-I-carrying cells MT-2 and MT-4 and application in a plaque assay. Science 1985, 229(4713):563-566.
• [72]Popovic M, Sarngadharan MG, Read E, Gallo RC: Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 1984, 224(4648):497-500.
• [73]Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D, Herdewijn P, Desmyter J, De Clercq E: Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods 1988, 20(4):309-321.
• [74]Bolstad BM, Irizarry RA, Astrand M, Speed TP: A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 2003, 19(2):185-193.