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Volumn 6, Issue 1, 2010, Pages

In vivo CD8+ T-cell suppression of SIV viremia is not mediated by CTL clearance of productively infected cells

Author keywords

[No Author keywords available]

Indexed keywords

EMTRICITABINE; GAG PROTEIN; NEF PROTEIN; TENOFOVIR; ANTIRETROVIRUS AGENT;

EID: 77649193824     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1000748     Document Type: Article
Times cited : (119)

References (44)
  • 1
    • 16944365445 scopus 로고    scopus 로고
    • Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus
    • Borrow P, Lewicki H, Wei X, Horwitz MS, Peffer N, et al. (1997) Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med 3: 205-211.
    • (1997) Nat Med , vol.3 , pp. 205-211
    • Borrow, P.1    Lewicki, H.2    Wei, X.3    Horwitz, M.S.4    Peffer, N.5
  • 2
    • 0028041344 scopus 로고
    • Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection
    • Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB (1994) Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 68: 6103-6110.
    • (1994) J Virol , vol.68 , pp. 6103-6110
    • Borrow, P.1    Lewicki, H.2    Hahn, B.H.3    Shaw, G.M.4    Oldstone, M.B.5
  • 3
    • 0028277886 scopus 로고
    • Development of the anti-gp120 antibody response during seroconversion to human immunodeficiency virus type 1
    • Moore JP, Cao Y, Ho DD, Koup RA (1994) Development of the anti-gp120 antibody response during seroconversion to human immunodeficiency virus type 1. J Virol 68: 5142-5155.
    • (1994) J Virol , vol.68 , pp. 5142-5155
    • Moore, J.P.1    Cao, Y.2    Ho, D.D.3    Koup, R.A.4
  • 4
    • 0028337166 scopus 로고
    • Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome
    • Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, et al. (1994) Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 68: 4650-4655.
    • (1994) J Virol , vol.68 , pp. 4650-4655
    • Koup, R.A.1    Safrit, J.T.2    Cao, Y.3    Andrews, C.A.4    McLeod, G.5
  • 5
    • 7144227284 scopus 로고    scopus 로고
    • Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA
    • Ogg GS, Jin X, Bonhoeffer S, Dunbar PR, Nowak MA, et al. (1998) Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279: 2103-2106.
    • (1998) Science , vol.279 , pp. 2103-2106
    • Ogg, G.S.1    Jin, X.2    Bonhoeffer, S.3    Dunbar, P.R.4    Nowak, M.A.5
  • 6
    • 0033524838 scopus 로고    scopus 로고
    • Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes
    • Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, et al. (1999) Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283: 857-860.
    • (1999) Science , vol.283 , pp. 857-860
    • Schmitz, J.E.1    Kuroda, M.J.2    Santra, S.3    Sasseville, V.G.4    Simon, M.A.5
  • 7
    • 0033559648 scopus 로고    scopus 로고
    • Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virusinfected macaques
    • Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, et al. (1999) Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virusinfected macaques. J Exp Med 189: 991-998.
    • (1999) J Exp Med , vol.189 , pp. 991-998
    • Jin, X.1    Bauer, D.E.2    Tuttleton, S.E.3    Lewin, S.4    Gettie, A.5
  • 8
    • 0031985775 scopus 로고    scopus 로고
    • Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques
    • Matano T, Shibata R, Siemon C, Connors M, Lane HC, et al. (1998) Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 72: 164-169.
    • (1998) J Virol , vol.72 , pp. 164-169
    • Matano, T.1    Shibata, R.2    Siemon, C.3    Connors, M.4    Lane, H.C.5
  • 9
    • 0037303113 scopus 로고    scopus 로고
    • Effect of humoral immune responses on controlling viremia during primary infection of rhesus monkeys with simian immunodeficiency virus
    • Schmitz JE, Kuroda MJ, Santra S, Simon MA, Lifton MA, et al. (2003) Effect of humoral immune responses on controlling viremia during primary infection of rhesus monkeys with simian immunodeficiency virus. J Virol 77: 2165-2173.
    • (2003) J Virol , vol.77 , pp. 2165-2173
    • Schmitz, J.E.1    Kuroda, M.J.2    Santra, S.3    Simon, M.A.4    Lifton, M.A.5
  • 10
    • 34249068954 scopus 로고    scopus 로고
    • An HIV vaccine-evolving concepts
    • Johnston MI, Fauci AS (2007) An HIV vaccine-evolving concepts. N Engl J Med 356: 2073-2081.
    • (2007) N Engl J Med , vol.356 , pp. 2073-2081
    • Johnston, M.I.1    Fauci, A.S.2
  • 11
    • 38749096240 scopus 로고    scopus 로고
    • The failed HIV Merck vaccine study: A step back or a launching point for future vaccine development?
    • Sekaly RP (2008) The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development? J Exp Med 205: 7-12.
    • (2008) J Exp Med , vol.205 , pp. 7-12
    • Sekaly, R.P.1
  • 13
    • 0028811974 scopus 로고
    • Viral dynamics in human immunodeficiency virus type 1 infection
    • Wei X, Ghosh SK, Taylor ME, Jonson VA, Emini EA, et al. (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373: 117-122.
    • (1995) Nature , vol.373 , pp. 117-122
    • Wei, X.1    Ghosh, S.K.2    Taylor, M.E.3    Jonson, V.A.4    Emini, E.A.5
  • 14
    • 0029967721 scopus 로고    scopus 로고
    • HIV-1 dynamics in vivo: Virion clearance rate, infected cell life-span, and viral generation time
    • Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD (1996) HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271: 1582-1586.
    • (1996) Science , vol.271 , pp. 1582-1586
    • Perelson, A.S.1    Neumann, A.U.2    Markowitz, M.3    Leonard, J.M.4    Ho, D.D.5
  • 15
    • 0028874048 scopus 로고
    • Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection
    • Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, et al. (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373: 123-126.
    • (1995) Nature , vol.373 , pp. 123-126
    • Ho, D.D.1    Neumann, A.U.2    Perelson, A.S.3    Chen, W.4    Leonard, J.M.5
  • 16
    • 0037444053 scopus 로고    scopus 로고
    • Determining the relative efficacy of highly active antiretroviral therapy
    • Louie M, Hogan C, Di Mascio M, Hurley A, Simon V, et al. (2003) Determining the relative efficacy of highly active antiretroviral therapy. J Infect Dis 187: 896-900.
    • (2003) J Infect Dis , vol.187 , pp. 896-900
    • Louie, M.1    Hogan, C.2    Di Mascio, M.3    Hurley, A.4    Simon, V.5
  • 17
    • 0035835505 scopus 로고    scopus 로고
    • Real-time TaqMan PCR as a specific and more sensitive alternative to the branched-chain DNA assay for quantitation of simian immunodeficiency virus RNA
    • Leutenegger CM, Higgins J, Matthews TB, Tarantal AF, Luciw PA, et al. (2001) Real-time TaqMan PCR as a specific and more sensitive alternative to the branched-chain DNA assay for quantitation of simian immunodeficiency virus RNA. AIDS Res Hum Retroviruses 17: 243-251.
    • (2001) AIDS Res Hum Retroviruses , vol.17 , pp. 243-251
    • Leutenegger, C.M.1    Higgins, J.2    Matthews, T.B.3    Tarantal, A.F.4    Luciw, P.A.5
  • 18
    • 13944258421 scopus 로고    scopus 로고
    • Early antiretroviral therapy for simian immunodeficiency virus infection leads to mucosal CD4+ Tcell restoration and enhanced gene expression regulating mucosal repair and regeneration
    • George MD, Reay E, Sankaran S, Dandekar S (2005) Early antiretroviral therapy for simian immunodeficiency virus infection leads to mucosal CD4+ Tcell restoration and enhanced gene expression regulating mucosal repair and regeneration. J Virol 79: 2709-2719.
    • (2005) J Virol , vol.79 , pp. 2709-2719
    • George, M.D.1    Reay, E.2    Sankaran, S.3    Dandekar, S.4
  • 19
    • 41949101136 scopus 로고    scopus 로고
    • Antiviral therapy during primary simian immunodeficiency virus infection fails to prevent acute loss of CD4+ T cells in gut mucosa but enhances their rapid restoration through central memory T cells
    • Verhoeven D, Sankaran S, Silvey M, Dandekar S (2008) Antiviral therapy during primary simian immunodeficiency virus infection fails to prevent acute loss of CD4+ T cells in gut mucosa but enhances their rapid restoration through central memory T cells. J Virol 82: 4016-4027.
    • (2008) J Virol , vol.82 , pp. 4016-4027
    • Verhoeven, D.1    Sankaran, S.2    Silvey, M.3    Dandekar, S.4
  • 20
    • 77649221355 scopus 로고    scopus 로고
    • Felsenstein J (1993) Phylogenetic Inference Package (Phylip) 3.5 University of Washington.
    • Felsenstein J (1993) Phylogenetic Inference Package (Phylip) 3.5 University of Washington.
  • 21
    • 0022507362 scopus 로고
    • Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions
    • Nei M, Gojobori T (1986) Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3: 418-426.
    • (1986) Mol Biol Evol , vol.3 , pp. 418-426
    • Nei, M.1    Gojobori, T.2
  • 22
    • 0030756525 scopus 로고    scopus 로고
    • Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection
    • Nowak MA, Lloyd AL, Vasquez GM, Wiltrout TA, Wahl LM, et al. (1997) Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection. J Virol 71: 7518-7525.
    • (1997) J Virol , vol.71 , pp. 7518-7525
    • Nowak, M.A.1    Lloyd, A.L.2    Vasquez, G.M.3    Wiltrout, T.A.4    Wahl, L.M.5
  • 23
    • 20744444986 scopus 로고    scopus 로고
    • Effect of CD8+ lymphocyte depletion on virus containment after simian immunodeficiency virus SIVmac251 challenge of live attenuated SIVmac239-delta3-vaccinated rhesus macaques
    • Schmitz JE, Johnson RP, McClure HM, Manson KH, Wyand MS, et al. (2005) Effect of CD8+ lymphocyte depletion on virus containment after simian immunodeficiency virus SIVmac251 challenge of live attenuated SIVmac239-delta3-vaccinated rhesus macaques. J Virol 79: 8131-8141.
    • (2005) J Virol , vol.79 , pp. 8131-8141
    • Schmitz, J.E.1    Johnson, R.P.2    McClure, H.M.3    Manson, K.H.4    Wyand, M.S.5
  • 24
    • 43949139261 scopus 로고    scopus 로고
    • Contribution of CD8+ T cells to containment of viral replication and emergence of mutations in Mamu-A*01-restricted epitopes in Simian immunodeficiency virus-infected rhesus monkeys
    • Kim EY, Veazey RS, Zahn R, McEvers KJ, Baumeister SH, et al. (2008) Contribution of CD8+ T cells to containment of viral replication and emergence of mutations in Mamu-A*01-restricted epitopes in Simian immunodeficiency virus-infected rhesus monkeys. J Virol 82: 5631-5635.
    • (2008) J Virol , vol.82 , pp. 5631-5635
    • Kim, E.Y.1    Veazey, R.S.2    Zahn, R.3    McEvers, K.J.4    Baumeister, S.H.5
  • 25
    • 50449090525 scopus 로고    scopus 로고
    • An HIV vaccine-challenges and prospects
    • Johnston MI, Fauci AS (2008) An HIV vaccine-challenges and prospects. N Engl J Med 359: 888-890.
    • (2008) N Engl J Med , vol.359 , pp. 888-890
    • Johnston, M.I.1    Fauci, A.S.2
  • 26
    • 0024502950 scopus 로고
    • A diffusable lymphokine produced by CD8+ T lymphocytes suppresses HIV replication
    • Walker CM, Levy JA (1989) A diffusable lymphokine produced by CD8+ T lymphocytes suppresses HIV replication. Immunology 66: 628.
    • (1989) Immunology , vol.66 , pp. 628
    • Walker, C.M.1    Levy, J.A.2
  • 27
    • 0022967777 scopus 로고
    • CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication
    • Walker CM, Moody DJ, Stites DP, Levy JA (1986) CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 234: 1563.
    • (1986) Science , vol.234 , pp. 1563
    • Walker, C.M.1    Moody, D.J.2    Stites, D.P.3    Levy, J.A.4
  • 28
    • 0029417004 scopus 로고
    • Identification of Rantes, MIP-1a, and MIP-1b as the major HIV-suppressive factors produced by CD8+ T-Cells
    • Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, et al. (1995) Identification of Rantes, MIP-1a, and MIP-1b as the major HIV-suppressive factors produced by CD8+ T-Cells. Science 270: 1811-1815.
    • (1995) Science , vol.270 , pp. 1811-1815
    • Cocchi, F.1    DeVico, A.L.2    Garzino-Demo, A.3    Arya, S.K.4    Gallo, R.C.5
  • 29
    • 33847388794 scopus 로고    scopus 로고
    • Gagspecific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression
    • Sacha JB, Chung C, Rakasz EG, Spencer SP, Jonas AK, et al. (2007) Gagspecific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression. J Immunol 178: 2746-2754.
    • (2007) J Immunol , vol.178 , pp. 2746-2754
    • Sacha, J.B.1    Chung, C.2    Rakasz, E.G.3    Spencer, S.P.4    Jonas, A.K.5
  • 30
    • 77649217418 scopus 로고    scopus 로고
    • Klatt NR, Shudo E, Ortiz AM, Engram JC, Paiardini M, et al. (2010) CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells. PLoS Pathog 6: e1000747. doi:10.1371/journal.ppat.1000747.
    • Klatt NR, Shudo E, Ortiz AM, Engram JC, Paiardini M, et al. (2010) CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells. PLoS Pathog 6: e1000747. doi:10.1371/journal.ppat.1000747.
  • 31
    • 67650457719 scopus 로고    scopus 로고
    • Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis
    • Okoye A, Park H, Rohankhedkar M, Coyne-Johnson L, Lum R, et al. (2009) Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis. J Exp Med 206: 1575-1588.
    • (2009) J Exp Med , vol.206 , pp. 1575-1588
    • Okoye, A.1    Park, H.2    Rohankhedkar, M.3    Coyne-Johnson, L.4    Lum, R.5
  • 33
    • 43249125709 scopus 로고    scopus 로고
    • Treatment response in acute/early infection versus advanced AIDS: Equivalent first and second phases of HIV RNA decline
    • Kilby JM, Lee HY, Hazelwood JD, Bansal A, Bucy RP, et al. (2008) Treatment response in acute/early infection versus advanced AIDS: equivalent first and second phases of HIV RNA decline. Aids 22: 957-962.
    • (2008) Aids , vol.22 , pp. 957-962
    • Kilby, J.M.1    Lee, H.Y.2    Hazelwood, J.D.3    Bansal, A.4    Bucy, R.P.5
  • 34
    • 0036784585 scopus 로고    scopus 로고
    • Human immunodeficiency virus-specific CD8(+) T-cell responses do not predict viral growth and clearance rates during structured intermittent antiretroviral therapy
    • Oxenius A, McLean AR, Fischer M, Price DA, Dawson SJ, et al. (2002) Human immunodeficiency virus-specific CD8(+) T-cell responses do not predict viral growth and clearance rates during structured intermittent antiretroviral therapy. J Virol 76: 10169-10176.
    • (2002) J Virol , vol.76 , pp. 10169-10176
    • Oxenius, A.1    McLean, A.R.2    Fischer, M.3    Price, D.A.4    Dawson, S.J.5
  • 35
    • 41149083421 scopus 로고    scopus 로고
    • Shortlived infected cells support virus replication in sooty mangabeys naturally infected with simian immunodeficiency virus: Implications for AIDS pathogenesis
    • Gordon SN, Dunham RM, Engram JC, Estes J, Wang Z, et al. (2008) Shortlived infected cells support virus replication in sooty mangabeys naturally infected with simian immunodeficiency virus: implications for AIDS pathogenesis. J Virol 82: 3725-3735.
    • (2008) J Virol , vol.82 , pp. 3725-3735
    • Gordon, S.N.1    Dunham, R.M.2    Engram, J.C.3    Estes, J.4    Wang, Z.5
  • 36
    • 33745627473 scopus 로고    scopus 로고
    • The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus
    • Dunham R, Pagliardini P, Gordon S, Sumpter B, Engram J, et al. (2006) The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus. Blood 108: 209-217.
    • (2006) Blood , vol.108 , pp. 209-217
    • Dunham, R.1    Pagliardini, P.2    Gordon, S.3    Sumpter, B.4    Engram, J.5
  • 37
    • 34250184098 scopus 로고    scopus 로고
    • Depletion of CD8+ cells in sooty mangabey monkeys naturally infected with simian immunodeficiency virus reveals limited role for immune control of virus replication in a natural host species
    • Barry AP, Silvestri G, Safrit JT, Sumpter B, Kozyr N, et al. (2007) Depletion of CD8+ cells in sooty mangabey monkeys naturally infected with simian immunodeficiency virus reveals limited role for immune control of virus replication in a natural host species. J Immunol 178: 8002-8012.
    • (2007) J Immunol , vol.178 , pp. 8002-8012
    • Barry, A.P.1    Silvestri, G.2    Safrit, J.T.3    Sumpter, B.4    Kozyr, N.5
  • 38
    • 0025853347 scopus 로고
    • Kinetics of expression of multiply spliced RNA in early human immunodeficiency virus type 1 infection of lymphocytes and monocytes
    • Klotman ME, Kim S, Buchbinder A, DeRossi A, Baltimore D, et al. (1991) Kinetics of expression of multiply spliced RNA in early human immunodeficiency virus type 1 infection of lymphocytes and monocytes. Proc Natl Acad Sci USA 88: 5011-5015.
    • (1991) Proc Natl Acad Sci USA , vol.88 , pp. 5011-5015
    • Klotman, M.E.1    Kim, S.2    Buchbinder, A.3    DeRossi, A.4    Baltimore, D.5
  • 39
    • 0024347717 scopus 로고
    • Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: Evidence for differential gene expression
    • Kim S-Y, Byrn R, Groopman J, Baltimore D (1989) Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: evidence for differential gene expression. Journal of Virology 63: 3708-3713.
    • (1989) Journal of Virology , vol.63 , pp. 3708-3713
    • Kim, S.-Y.1    Byrn, R.2    Groopman, J.3    Baltimore, D.4
  • 40
    • 0033030828 scopus 로고    scopus 로고
    • HIV's evasion of the cellular immune response
    • Collins KL, Baltimore D (1999) HIV's evasion of the cellular immune response. Immunol Rev 168: 65-74.
    • (1999) Immunol Rev , vol.168 , pp. 65-74
    • Collins, K.L.1    Baltimore, D.2
  • 41
    • 0032556872 scopus 로고    scopus 로고
    • HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes
    • Collins KL, Chen BK, Kalams SA, Walker BD, Baltimore D (1998) HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391: 397-401.
    • (1998) Nature , vol.391 , pp. 397-401
    • Collins, K.L.1    Chen, B.K.2    Kalams, S.A.3    Walker, B.D.4    Baltimore, D.5
  • 42
    • 35348873159 scopus 로고    scopus 로고
    • Productive human immunodeficiency virus type 1 infection in peripheral blood predominantly takes place in CD4/CD8 double-negative T lymphocytes
    • Kaiser P, Joos B, Niederost B, Weber R, Gunthard HF, et al. (2007) Productive human immunodeficiency virus type 1 infection in peripheral blood predominantly takes place in CD4/CD8 double-negative T lymphocytes. J Virol 81: 9693-9706.
    • (2007) J Virol , vol.81 , pp. 9693-9706
    • Kaiser, P.1    Joos, B.2    Niederost, B.3    Weber, R.4    Gunthard, H.F.5
  • 43
    • 33845288582 scopus 로고    scopus 로고
    • Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection
    • Huber M, Fischer M, Misselwitz B, Manrique A, Kuster H, et al. (2006) Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection. PLoS Med 3: e441.
    • (2006) PLoS Med , vol.3
    • Huber, M.1    Fischer, M.2    Misselwitz, B.3    Manrique, A.4    Kuster, H.5
  • 44
    • 33748612442 scopus 로고    scopus 로고
    • NK cell function in HIV-1 infection
    • Alter G, Altfeld M (2006) NK cell function in HIV-1 infection. Curr Mol Med 6: 621-629.
    • (2006) Curr Mol Med , vol.6 , pp. 621-629
    • Alter, G.1    Altfeld, M.2


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