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Annual Review of Virology

Volume 2, 2015

Innate and Adaptive Immune Regulation During Chronic Viral Infections

Abstract

Chronic viral infections represent a unique challenge to the infected host. Persistently replicating viruses outcompete or subvert the initial antiviral response, allowing the establishment of chronic infections that result in continuous stimulation of both the innate and adaptive immune compartments. This causes a profound reprogramming of the host immune system, including attenuation and persistent low levels of type I interferons, progressive loss (or exhaustion) of CD8+ T cell functions, and specialization of CD4+ T cells to produce interleukin-21 and promote antibody-mediated immunity and immune regulation. Epigenetic, transcriptional, posttranscriptional, and metabolic changes underlie this adaptation or recalibration of immune cells to the emerging new environment in order to strike an often imperfect balance between the host and the infectious pathogen. In this review we discuss the common immunological hallmarks observed across a range of different persistently replicating viruses and host species, the underlying molecular mechanisms, and the biological and clinical implications.

Keyword(s): chronic viral infection, HCV, HIV, interferon, LCMV, T cells
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/content/journals/10.1146/annurev-virology-100114-055226
2015-11-09
2024-04-19
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Literature Cited

  1. Kassiotis G. 1.  2014. Endogenous retroviruses and the development of cancer. J. Immunol. 192:1343–49 [Google Scholar]
  2. Virgin HW, Wherry EJ, Ahmed R. 2.  2009. Redefining chronic viral infection. Cell 138:30–50 [Google Scholar]
  3. Aoshi T, Koyama S, Kobiyama K, Akira S, Ishii KJ. 3.  2011. Innate and adaptive immune responses to viral infection and vaccination. Curr. Opin. Virol. 1:226–32 [Google Scholar]
  4. Garcia-Sastre A, Biron CA. 4.  2006. Type 1 interferons and the virus-host relationship: a lesson in détente. Science 312:879–82 [Google Scholar]
  5. Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E. 5.  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. 83:3719–33 [Google Scholar]
  6. Zuniga EI, Liou LY, Mack L, Mendoza M, Oldstone MB. 6.  2008. Persistent virus infection inhibits type I interferon production by plasmacytoid dendritic cells to facilitate opportunistic infections. Cell Host Microbe 4:374–86 [Google Scholar]
  7. Bosinger SE, Li Q, Gordon SN, Klatt NR, Duan L. 7.  et al. 2009. Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. J. Clin. Investig. 119:3556–72 [Google Scholar]
  8. Clingan JM, Ostrow K, Hosiawa KA, Chen ZJ, Matloubian M. 8.  2012. Differential roles for RIG-I-like receptors and nucleic acid-sensing TLR pathways in controlling a chronic viral infection. J. Immunol. 188:4432–40 [Google Scholar]
  9. Jacquelin B, Mayau V, Targat B, Liovat AS, Kunkel D. 9.  et al. 2009. Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J. Clin. Investig. 119:3544–55 [Google Scholar]
  10. Wilson EB, Yamada DH, Elsaesser H, Herskovitz J, Deng J. 10.  et al. 2013. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340:202–7 [Google Scholar]
  11. Wieland S, Thimme R, Purcell RH, Chisari FV. 11.  2004. Genomic analysis of the host response to hepatitis B virus infection. PNAS 101:6669–74 [Google Scholar]
  12. Hahm B, Trifilo MJ, Zuniga EI, Oldstone MB. 12.  2005. Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling. Immunity 22:247–57 [Google Scholar]
  13. Diebold SS, Montoya M, Unger H, Alexopoulou L, Roy P. 13.  et al. 2003. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424:324–28 [Google Scholar]
  14. Wang Y, Swiecki M, Cella M, Alber G, Schreiber RD. 14.  et al. 2012. Timing and magnitude of type I interferon responses by distinct sensors impact CD8 T cell exhaustion and chronic viral infection. Cell Host Microbe 11:631–42 [Google Scholar]
  15. Schoggins JW, Rice CM. 15.  2013. Innate immune responses to hepatitis C virus. Curr. Top. Microbiol. Immunol. 369:219–42 [Google Scholar]
  16. Silvin A, Manel N. 16.  2015. Innate immune sensing of HIV infection. Curr. Opin. Immunol. 32:54–60 [Google Scholar]
  17. Reizis B, Bunin A, Ghosh HS, Lewis KL, Sisirak V. 17.  2011. Plasmacytoid dendritic cells: recent progress and open questions. Annu. Rev. Immunol. 29:163–83 [Google Scholar]
  18. Fitzgerald-Bocarsly P, Jacobs ES. 18.  2010. Plasmacytoid dendritic cells in HIV infection: striking a delicate balance. J. Leukoc. Biol. 87:609–20 [Google Scholar]
  19. Macal M, Lewis GM, Kunz S, Flavell R, Harker JA, Zuniga EI. 19.  2012. Plasmacytoid dendritic cells are productively infected and activated through TLR-7 early after arenavirus infection. Cell Host Microbe 11:617–30 [Google Scholar]
  20. Takahashi K, Asabe S, Wieland S, Garaigorta U, Gastaminza P. 20.  et al. 2010. Plasmacytoid dendritic cells sense hepatitis C virus-infected cells, produce interferon, and inhibit infection. PNAS 107:7431–36 [Google Scholar]
  21. Cervantes-Barragan L, Lewis KL, Firner S, Thiel V, Hugues S. 21.  et al. 2012. Plasmacytoid dendritic cells control T-cell response to chronic viral infection. PNAS 109:3012–17 [Google Scholar]
  22. Dreux M, Garaigorta U, Boyd B, Decembre E, Chung J. 22.  et al. 2012. Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host Microbe 12:558–70 [Google Scholar]
  23. Lee LN, Burke S, Montoya M, Borrow P. 23.  2009. Multiple mechanisms contribute to impairment of type 1 interferon production during chronic lymphocytic choriomeningitis virus infection of mice. J. Immunol. 182:7178–89 [Google Scholar]
  24. Dolganiuc A, Chang S, Kodys K, Mandrekar P, Bakis G. 24.  et al. 2006. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-α and plasmacytoid dendritic cell loss in chronic HCV infection. J. Immunol. 177:6758–68 [Google Scholar]
  25. Rotger M, Dalmau J, Rauch A, McLaren P, Bosinger SE. 25.  et al. 2011. Comparative transcriptomics of extreme phenotypes of human HIV-1 infection and SIV infection in sooty mangabey and rhesus macaque. J. Clin. Investig. 121:2391–400 [Google Scholar]
  26. Su AI, Pezacki JP, Wodicka L, Brideau AD, Supekova L. 26.  et al. 2002. Genomic analysis of the host response to hepatitis C virus infection. PNAS 99:15669–74 [Google Scholar]
  27. Foy E, Li K, Sumpter R Jr, Loo YM, Johnson CL. 27.  et al. 2005. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. PNAS 102:2986–91 [Google Scholar]
  28. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon AC. 28.  et al. 2005. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. PNAS 102:2992–97 [Google Scholar]
  29. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M. 29.  et al. 2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–72 [Google Scholar]
  30. Martinez-Sobrido L, Zuniga EI, Rosario D, Garcia-Sastre A, de la Torre JC. 30.  2006. Inhibition of the type I interferon response by the nucleoprotein of the prototypic arenavirus lymphocytic choriomeningitis virus. J. Virol. 80:9192–99 [Google Scholar]
  31. Okumura A, Alce T, Lubyova B, Ezelle H, Strebel K, Pitha PM. 31.  2008. HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation. Virology 373:85–97 [Google Scholar]
  32. Martinelli E, Cicala C, Van Ryk D, Goode DJ, Macleod K. 32.  et al. 2007. HIV-1 gp120 inhibits TLR9-mediated activation and IFN-α secretion in plasmacytoid dendritic cells. PNAS 104:3396–401 [Google Scholar]
  33. Rasaiyaah J, Tan CP, Fletcher AJ, Price AJ, Blondeau C. 33.  et al. 2013. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503:402–5 [Google Scholar]
  34. Kumar M, Jung SY, Hodgson AJ, Madden CR, Qin J, Slagle BL. 34.  2011. Hepatitis B virus regulatory HBx protein binds to adaptor protein IPS-1 and inhibits the activation of beta interferon. J. Virol. 85:987–95 [Google Scholar]
  35. Wang X, Li Y, Mao A, Li C, Tien P. 35.  2010. Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex. Cell. Mol. Immunol. 7:341–48 [Google Scholar]
  36. Wei C, Ni C, Song T, Liu Y, Yang X. 36.  et al. 2010. The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. J. Immunol. 185:1158–68 [Google Scholar]
  37. Yu S, Chen J, Wu M, Chen H, Kato N, Yuan Z. 37.  2010. Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKε and DDX3. J. Gen. Virol. 91:2080–90 [Google Scholar]
  38. Visvanathan K, Skinner NA, Thompson AJ, Riordan SM, Sozzi V. 38.  et al. 2007. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology 45:102–10 [Google Scholar]
  39. Xie Q, Shen HC, Jia NN, Wang H, Lin LY. 39.  et al. 2009. Patients with chronic hepatitis B infection display deficiency of plasmacytoid dendritic cells with reduced expression of TLR9. Microbes Infect. 11:515–23 [Google Scholar]
  40. Xu Y, Hu Y, Shi B, Zhang X, Wang J. 40.  et al. 2009. HBsAg inhibits TLR9-mediated activation and IFN-α production in plasmacytoid dendritic cells. Mol. Immunol. 46:2640–46 [Google Scholar]
  41. Dolganiuc A, Norkina O, Kodys K, Catalano D, Bakis G. 41.  et al. 2007. Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection. Gastroenterology 133:1627–36 [Google Scholar]
  42. Negash AA, Ramos HJ, Crochet N, Lau DT, Doehle B. 42.  et al. 2013. IL-1β production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. PLOS Pathog. 9:e1003330 [Google Scholar]
  43. Brown JN, Kohler JJ, Coberley CR, Sleasman JW, Goodenow MM. 43.  2008. HIV-1 activates macrophages independent of Toll-like receptors. PLOS ONE 3:e3664 [Google Scholar]
  44. Nagy LH, Grishina I, Macal M, Hirao LA, Hu WK. 44.  et al. 2013. Chronic HIV infection enhances the responsiveness of antigen presenting cells to commensal Lactobacillus. PLOS ONE 8e72789
  45. Crouse J, Bedenikovic G, Wiesel M, Ibberson M, Xenarios I. 45.  et al. 2014. Type I interferons protect T cells against NK cell attack mediated by the activating receptor NCR1. Immunity 40:961–73 [Google Scholar]
  46. Ou R, Zhou S, Huang L, Moskophidis D. 46.  2001. Critical role for alpha/beta and gamma interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells. J. Virol. 75:8407–23 [Google Scholar]
  47. Sandler NG, Bosinger SE, Estes JD, Zhu RT, Tharp GK. 47.  et al. 2014. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature 511:601–5 [Google Scholar]
  48. Borrow P. 48.  2011. Innate immunity in acute HIV-1 infection. Curr. Opin. HIV AIDS 6:353–63 [Google Scholar]
  49. Asmuth DM, Murphy RL, Rosenkranz SL, Lertora JJ, Kottilil S. 49.  et al. 2010. 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. 201:1686–96 [Google Scholar]
  50. Azzoni L, Foulkes AS, Papasavvas E, Mexas AM, Lynn KM. 50.  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. 207:213–22 [Google Scholar]
  51. Boue F, Reynes J, Rouzioux C, Emilie D, Souala F. 51.  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 25:115–18 [Google Scholar]
  52. Hatzakis A, Gargalianos P, Kiosses V, Lazanas M, Sypsa V. 52.  et al. 2001. Low-dose IFN-α monotherapy in treatment-naive individuals with HIV-1 infection: evidence of potent suppression of viral replication. J. Interferon Cytokine Res. 21:861–69 [Google Scholar]
  53. Laidlaw SM, Dustin LB. 53.  2014. Interferon lambda: opportunities, risks, and uncertainties in the fight against HCV. Front. Immunol. 5:545 [Google Scholar]
  54. Sarasin-Filipowicz M, Oakeley EJ, Duong FH, Christen V, Terracciano L. 54.  et al. 2008. Interferon signaling and treatment outcome in chronic hepatitis C. PNAS 105:7034–39 [Google Scholar]
  55. Harris LD, Tabb B, Sodora DL, Paiardini M, Klatt NR. 55.  et al. 2010. Downregulation of robust acute type I interferon responses distinguishes nonpathogenic simian immunodeficiency virus (SIV) infection of natural hosts from pathogenic SIV infection of rhesus macaques. J. Virol. 84:7886–91 [Google Scholar]
  56. Durudas A, Milush JM, Chen HL, Engram JC, Silvestri G, Sodora DL. 56.  2009. Elevated levels of innate immune modulators in lymph nodes and blood are associated with more-rapid disease progression in simian immunodeficiency virus-infected monkeys. J. Virol. 83:12229–40 [Google Scholar]
  57. Rotger M, Dang KK, Fellay J, Heinzen EL, Feng S. 57.  et al. 2010. Genome-wide mRNA expression correlates of viral control in CD4+ T-cells from HIV-1-infected individuals. PLOS Pathog. 6:e1000781 [Google Scholar]
  58. Herbeuval JP, Nilsson J, Boasso A, Hardy AW, Kruhlak MJ. 58.  et al. 2006. Differential expression of IFN-α and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients. PNAS 103:7000–5 [Google Scholar]
  59. Teijaro JR, Ng C, Lee AM, Sullivan BM, Sheehan KC. 59.  et al. 2013. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 340:207–11 [Google Scholar]
  60. Kodama A, Tanaka R, Zhang LF, Adachi T, Saito M. 60.  et al. 2010. Impairment of in vitro generation of monocyte-derived human dendritic cells by inactivated human immunodeficiency virus-1: involvement of type I interferon produced from plasmacytoid dendritc cells. Hum. Immunol. 71:541–50 [Google Scholar]
  61. Sevilla N, McGavern DB, Teng C, Kunz S, Oldstone MB. 61.  2004. Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion. J. Clin. Investig. 113:737–45 [Google Scholar]
  62. Herbeuval JP, Grivel JC, Boasso A, Hardy AW, Chougnet C. 62.  et al. 2005. CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis. Blood 106:3524–31 [Google Scholar]
  63. Matloubian M, Concepcion RJ, Ahmed R. 63.  1994. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J. Virol. 68:8056–63 [Google Scholar]
  64. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA. 64.  et al. 1999. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283:857–60 [Google Scholar]
  65. Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A. 65.  et al. 1999. Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques. J. Exp. Med. 189:991–98 [Google Scholar]
  66. Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV. 66.  et al. 2012. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338:1220–25 [Google Scholar]
  67. Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA. 67.  et al. 2003. CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J. Virol. 77:68–76 [Google Scholar]
  68. Maini MK, Boni C, Ogg GS, King AS, Reignat S. 68.  et al. 1999. Direct ex vivo analysis of hepatitis B virus-specific CD8+ T cells associated with the control of infection. Gastroenterology 117:1386–96 [Google Scholar]
  69. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. 69.  1994. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J. Virol. 68:6103–10 [Google Scholar]
  70. Edwards BH, Bansal A, Sabbaj S, Bakari J, Mulligan MJ, Goepfert PA. 70.  2002. Magnitude of functional CD8+ T-cell responses to the Gag protein of human immunodeficiency virus type 1 correlates inversely with viral load in plasma. J. Virol. 76:2298–305 [Google Scholar]
  71. Jagannathan P, Osborne CM, Royce C, Manion MM, Tilton JC. 71.  et al. 2009. Comparisons of CD8+ T cells specific for human immunodeficiency virus, hepatitis C virus, and cytomegalovirus reveal differences in frequency, immunodominance, phenotype, and interleukin-2 responsiveness. J. Virol. 83:2728–42 [Google Scholar]
  72. Horton H, Frank I, Baydo R, Jalbert E, Penn J. 72.  et al. 2006. Preservation of T cell proliferation restricted by protective HLA alleles is critical for immune control of HIV-1 infection. J. Immunol. 177:7406–15 [Google Scholar]
  73. Price DA, Goulder PJ, Klenerman P, Sewell AK, Easterbrook PJ. 73.  et al. 1997. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. PNAS 94:1890–95 [Google Scholar]
  74. Blattman JN, Wherry EJ, Ha SJ, van der Most RG, Ahmed R. 74.  2009. Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection. J. Virol. 83:4386–94 [Google Scholar]
  75. Wherry EJ. 75.  2011. T cell exhaustion. Nat. Immunol. 12:492–99 [Google Scholar]
  76. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M. 76.  et al. 1998. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188:2205–13 [Google Scholar]
  77. Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. 77.  2003. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77:4911–27 [Google Scholar]
  78. Jo J, Bengsch B, Seigel B, Rau SJ, Schmidt J. 78.  et al. 2012. Low perforin expression of early differentiated HCV-specific CD8+ T cells limits their hepatotoxic potential. J. Hepatol. 57:9–16 [Google Scholar]
  79. Zhang D, Shankar P, Xu Z, Harnisch B, Chen G. 79.  et al. 2003. Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic. Blood 101:226–35 [Google Scholar]
  80. Wherry EJ, Barber DL, Kaech SM, Blattman JN, Ahmed R. 80.  2004. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. PNAS 101:16004–9 [Google Scholar]
  81. Wherry EJ, Day CL, Draenert R, Miller JD, Kiepiela P. 81.  et al. 2006. HIV-specific CD8 T cells express low levels of IL-7Rα: implications for HIV-specific T cell memory. Virology 353:366–73 [Google Scholar]
  82. Utzschneider DT, Legat A, Fuertes Marraco SA, Carrie L, Luescher I. 82.  et al. 2013. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat. Immunol. 14:603–10 [Google Scholar]
  83. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ. 83.  et al. 2009. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10:29–37 [Google Scholar]
  84. Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M. 84.  et al. 2010. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLOS Pathog. 6:e1000947 [Google Scholar]
  85. Schlaphoff V, Lunemann S, Suneetha PV, Jaroszewicz J, Grabowski J. 85.  et al. 2011. Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells. PLOS Pathog. 7:e1002045 [Google Scholar]
  86. Yamamoto T, Price DA, Casazza JP, Ferrari G, Nason M. 86.  et al. 2011. Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection. Blood 117:4805–15 [Google Scholar]
  87. Nakamoto N, Kaplan DE, Coleclough J, Li Y, Valiga ME. 87.  et al. 2008. Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 134:1927–37 [Google Scholar]
  88. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S. 88.  et al. 2006. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12:1198–202 [Google Scholar]
  89. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES. 89.  et al. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350–54 [Google Scholar]
  90. Fuller MJ, Hildeman DA, Sabbaj S, Gaddis DE, Tebo AE. 90.  et al. 2005. Cutting edge: emergence of CD127high functionally competent memory T cells is compromised by high viral loads and inadequate T cell help. J. Immunol. 174:5926–30 [Google Scholar]
  91. Blattman JN, Grayson JM, Wherry EJ, Kaech SM, Smith KA, Ahmed R. 91.  2003. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat. Med. 9:540–47 [Google Scholar]
  92. Shin H, Blackburn SD, Blattman JN, Wherry EJ. 92.  2007. Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J. Exp. Med. 204:941–49 [Google Scholar]
  93. Ingram JT, Yi JS, Zajac AJ. 93.  2011. Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections. PLOS Pathog. 7:e1002273 [Google Scholar]
  94. Elrefaei M, Burke CM, Baker CA, Jones NG, Bousheri S. 94.  et al. 2009. TGF-β and IL-10 production by HIV-specific CD8+ T cells is regulated by CTLA-4 signaling on CD4+ T cells. PLOS ONE 4:e8194 [Google Scholar]
  95. Brockman MA, Kwon DS, Tighe DP, Pavlik DF, Rosato PC. 95.  et al. 2009. IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood 114:346–56 [Google Scholar]
  96. Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MB. 96.  2006. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12:1301–9 [Google Scholar]
  97. Tinoco R, Alcalde V, Yang Y, Sauer K, Zuniga EI. 97.  2009. Cell-intrinsic transforming growth factor-β signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity 31:145–57 [Google Scholar]
  98. Alatrakchi N, Graham CS, van der Vliet HJ, Sherman KE, Exley MA, Koziel MJ. 98.  2007. Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor β that can suppress HCV-specific T-cell responses. J. Virol. 81:5882–92 [Google Scholar]
  99. Brooks DG, McGavern DB, Oldstone MB. 99.  2006. Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection. J. Clin. Investig. 116:1675–85 [Google Scholar]
  100. Mueller SN, Ahmed R. 100.  2009. High antigen levels are the cause of T cell exhaustion during chronic viral infection. PNAS 106:8623–28 [Google Scholar]
  101. Richter K, Brocker T, Oxenius A. 101.  2012. Antigen amount dictates CD8+ T-cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell. Eur. J. Immunol. 42:2290–304 [Google Scholar]
  102. Oxenius A, Sewell AK, Dawson SJ, Gunthard HF, Fischer M. 102.  et al. 2002. Functional discrepancies in HIV-specific CD8+ T-lymphocyte populations are related to plasma virus load. J. Clin. Immunol. 22:363–74 [Google Scholar]
  103. Rehr M, Cahenzli J, Haas A, Price DA, Gostick E. 103.  et al. 2008. Emergence of polyfunctional CD8+ T cells after prolonged suppression of human immunodeficiency virus replication by antiretroviral therapy. J. Virol. 82:3391–404 [Google Scholar]
  104. Lechner F, Gruener NH, Urbani S, Uggeri J, Santantonio T. 104.  et al. 2000. CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained. Eur. J. Immunol. 30:2479–87 [Google Scholar]
  105. Lichterfeld M, Yu XG, Mui SK, Williams KL, Trocha A. 105.  et al. 2007. Selective depletion of high-avidity human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells after early HIV-1 infection. J. Virol. 81:4199–214 [Google Scholar]
  106. Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, Wherry EJ. 106.  2012. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37:1130–44 [Google Scholar]
  107. Larsson M, Shankar EM, Che KF, Saeidi A, Ellegard R. 107.  et al. 2013. Molecular signatures of T-cell inhibition in HIV-1 infection. Retrovirology 10:31 [Google Scholar]
  108. Wirth TC, Xue HH, Rai D, Sabel JT, Bair T. 108.  et al. 2010. Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8+ T cell differentiation. Immunity 33:128–40 [Google Scholar]
  109. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S. 109.  et al. 2007. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27:670–84 [Google Scholar]
  110. Gaiha GD, McKim KJ, Woods M, Pertel T, Rohrbach J. 110.  et al. 2014. Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis. Immunity 41:1001–12 [Google Scholar]
  111. Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C. 111.  et al. 2010. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat. Med. 16:1147–51 [Google Scholar]
  112. Shin H, Blackburn SD, Intlekofer AM, Kao C, Angelosanto JM. 112.  et al. 2009. A role for the transcriptional repressor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection. Immunity 31:309–20 [Google Scholar]
  113. Agnellini P, Wolint P, Rehr M, Cahenzli J, Karrer U, Oxenius A. 113.  2007. Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection. PNAS 104:4565–70 [Google Scholar]
  114. Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM. 114.  et al. 2011. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat. Immunol. 12:663–71 [Google Scholar]
  115. Buggert M, Tauriainen J, Yamamoto T, Frederiksen J, Ivarsson MA. 115.  et al. 2014. T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLOS Pathog. 10:e1004251 [Google Scholar]
  116. Kurktschiev PD, Raziorrouh B, Schraut W, Backmund M, Wachtler M. 116.  et al. 2014. Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction. J. Exp. Med. 211:2047–59 [Google Scholar]
  117. Ribeiro-dos-Santos P, Turnbull EL, Monteiro M, Legrand A, Conrod K. 117.  et al. 2012. Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T-cell differentiation into cytolytic effectors. Blood 119:4928–38 [Google Scholar]
  118. Hersperger AR, Martin JN, Shin LY, Sheth PM, Kovacs CM. 118.  et al. 2011. Increased HIV-specific CD8+ T-cell cytotoxic potential in HIV elite controllers is associated with T-bet expression. Blood 117:3799–808 [Google Scholar]
  119. Parish IA, Marshall HD, Staron MM, Lang PA, Brustle A. 119.  et al. 2014. Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1. J. Clin. Investig. 124:3455–68 [Google Scholar]
  120. Martinez GJ, Pereira RM, Aijo T, Kim EY, Marangoni F. 120.  et al. 2015. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity 42:265–78 [Google Scholar]
  121. Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA. 121.  et al. 2004. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Lett. 574:37–41 [Google Scholar]
  122. Zinselmeyer BH, Heydari S, Sacristan C, Nayak D, Cammer M. 122.  et al. 2013. PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis. J. Exp. Med. 210:757–74 [Google Scholar]
  123. Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH. 123.  et al. 2014. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8 T cells during chronic infection. Immunity 41:802–14 [Google Scholar]
  124. Trautmann L, Mbitikon-Kobo FM, Goulet JP, Peretz Y, Shi Y. 124.  et al. 2012. Profound metabolic, functional, and cytolytic differences characterize HIV-specific CD8 T cells in primary and chronic HIV infection. Blood 120:3466–77 [Google Scholar]
  125. Schurich A, Henson SM. 125.  2014. The many unknowns concerning the bioenergetics of exhaustion and senescence during chronic viral infection. Front. Immunol. 5:468 [Google Scholar]
  126. Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV. 126.  et al. 2013. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153:1239–51 [Google Scholar]
  127. Mackerness KJ, Cox MA, Lilly LM, Weaver CT, Harrington LE, Zajac AJ. 127.  2010. Pronounced virus-dependent activation drives exhaustion but sustains IFN-γ transcript levels. J. Immunol. 185:3643–51 [Google Scholar]
  128. Sullivan JA, Kim EH, Plisch EH, Suresh M. 128.  2012. FOXO3 regulates the CD8 T cell response to a chronic viral infection. J. Virol. 86:9025–34 [Google Scholar]
  129. Finlay DK, Rosenzweig E, Sinclair LV, Feijoo-Carnero C, Hukelmann JL. 129.  et al. 2012. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209:2441–53 [Google Scholar]
  130. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV. 130.  et al. 2013. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 14:1173–82 [Google Scholar]
  131. Kim J, Kundu M, Viollet B, Guan KL. 131.  2011. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13:132–41 [Google Scholar]
  132. Xu X, Araki K, Li S, Han JH, Ye L. 132.  et al. 2014. Autophagy is essential for effector CD8+ T cell survival and memory formation. Nat. Immunol. 15:1152–61 [Google Scholar]
  133. Angelosanto JM, Blackburn SD, Crawford A, Wherry EJ. 133.  2012. Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J. Virol. 86:8161–70 [Google Scholar]
  134. Youngblood B, Noto A, Porichis F, Akondy RS, Ndhlovu ZM. 134.  et al. 2013. Cutting edge: Prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells. J. Immunol. 191:540–44 [Google Scholar]
  135. Youngblood B, Oestreich KJ, Ha SJ, Duraiswamy J, Akondy RS. 135.  et al. 2011. Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8+ T cells. Immunity 35:400–12 [Google Scholar]
  136. Zhang F, Zhou X, DiSpirito JR, Wang C, Wang Y, Shen H. 136.  2014. Epigenetic manipulation restores functions of defective CD8+ T cells from chronic viral infection. Mol. Ther. 22:1698–706 [Google Scholar]
  137. Rasmussen TA, Tolstrup M, Winckelmann A, Ostergaard L, Sogaard OS. 137.  2013. Eliminating the latent HIV reservoir by reactivation strategies: advancing to clinical trials. Hum. Vaccines Immunother. 9:790–99 [Google Scholar]
  138. Cox MA, Kahan SM, Zajac AJ. 138.  2013. Anti-viral CD8 T cells and the cytokines that they love. Virology 435:157–69 [Google Scholar]
  139. Nanjappa SG, Kim EH, Suresh M. 139.  2011. Immunotherapeutic effects of IL-7 during a chronic viral infection in mice. Blood 117:5123–32 [Google Scholar]
  140. Pellegrini M, Calzascia T, Toe JG, Preston SP, Lin AE. 140.  et al. 2011. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144:601–13 [Google Scholar]
  141. Pellegrini M, Calzascia T, Elford AR, Shahinian A, Lin AE. 141.  et al. 2009. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat. Med. 15:528–36 [Google Scholar]
  142. Yi JS, Du M, Zajac AJ. 142.  2009. A vital role for interleukin-21 in the control of a chronic viral infection. Science 324:1572–76 [Google Scholar]
  143. Keating SM, Jacobs ES, Norris PJ. 143.  2012. Soluble mediators of inflammation in HIV and their implications for therapeutics and vaccine development. Cytokine Growth Factor Rev. 23:193–206 [Google Scholar]
  144. Lugli E, Mueller YM, Lewis MG, Villinger F, Katsikis PD, Roederer M. 144.  2011. IL-15 delays suppression and fails to promote immune reconstitution in virally suppressed chronically SIV-infected macaques. Blood 118:2520–29 [Google Scholar]
  145. Mueller YM, Do DH, Altork SR, Artlett CM, Gracely EJ. 145.  et al. 2008. IL-15 treatment during acute simian immunodeficiency virus (SIV) infection increases viral set point and accelerates disease progression despite the induction of stronger SIV-specific CD8+ T cell responses. J. Immunol. 180:350–60 [Google Scholar]
  146. Pallikkuth S, Rogers K, Villinger F, Dosterii M, Vaccari M. 146.  et al. 2011. Interleukin-21 administration to rhesus macaques chronically infected with simian immunodeficiency virus increases cytotoxic effector molecules in T cells and NK cells and enhances B cell function without increasing immune activation or viral replication. Vaccine 29:9229–38 [Google Scholar]
  147. Brooks DG, Ha SJ, Elsaesser H, Sharpe AH, Freeman GJ, Oldstone MB. 147.  2008. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. PNAS 105:20428–33 [Google Scholar]
  148. Blackburn SD, Shin H, Freeman GJ, Wherry EJ. 148.  2008. Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. PNAS 105:15016–21 [Google Scholar]
  149. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP. 149.  et al. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–87 [Google Scholar]
  150. Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM. 150.  et al. 2006. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 203:2461–72 [Google Scholar]
  151. Garidou L, Heydari S, Gossa S, McGavern DB. 151.  2012. Therapeutic blockade of transforming growth factor beta fails to promote clearance of a persistent viral infection. J. Virol. 86:7060–71 [Google Scholar]
  152. Boettler T, Cheng Y, Ehrhardt K, von Herrath M. 152.  2012. TGF-β blockade does not improve control of an established persistent viral infection. Viral. Immunol. 25:232–38 [Google Scholar]
  153. Jin HT, Anderson AC, Tan WG, West EE, Ha SJ. 153.  et al. 2010. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. PNAS 107:14733–38 [Google Scholar]
  154. Vezys V, Penaloza-MacMaster P, Barber DL, Ha SJ, Konieczny B. 154.  et al. 2011. 4-1BB signaling synergizes with programmed death ligand 1 blockade to augment CD8 T cell responses during chronic viral infection. J. Immunol. 187:1634–42 [Google Scholar]
  155. Boettler T, Choi YS, Salek-Ardakani S, Cheng Y, Moeckel F. 155.  et al. 2013. Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts CD4 T cells into the effector lineage by upregulating Blimp-1. J. Immunol. 191:5026–35 [Google Scholar]
  156. West EE, Jin HT, Rasheed AU, Penaloza-MacMaster P, Ha SJ. 156.  et al. 2013. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J. Clin. Investig. 123:2604–15 [Google Scholar]
  157. Gardiner D, Lalezari J, Lawitz E, DiMicco M, Ghalib R. 157.  et al. 2013. A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. PLOS ONE 8:e63818 [Google Scholar]
  158. Porichis F, Kaufmann DE. 158.  2011. HIV-specific CD4 T cells and immune control of viral replication. Curr. Opin. HIV AIDS 6:174–80 [Google Scholar]
  159. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. 159.  2001. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J. Exp. Med. 194:1395–406 [Google Scholar]
  160. Diepolder HM, Zachoval R, Hoffmann RM, Wierenga EA, Santantonio T. 160.  et al. 1995. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 346:1006–7 [Google Scholar]
  161. Loggi E, Gamal N, Bihl F, Bernardi M, Andreone P. 161.  2014. Adaptive response in hepatitis B virus infection. J. Viral. Hepatol. 21:305–13 [Google Scholar]
  162. Julg B, Moodley ES, Qi Y, Ramduth D, Reddy S. 162.  et al. 2011. Possession of HLA class II DRB1*1303 associates with reduced viral loads in chronic HIV-1 clade C and B infection. J. Infect. Dis. 203:803–9 [Google Scholar]
  163. Ranasinghe S, Cutler S, Davis I, Lu R, Soghoian DZ. 163.  et al. 2013. Association of HLA-DRB1-restricted CD4+ T cell responses with HIV immune control. Nat. Med. 19:930–33 [Google Scholar]
  164. Grakoui A, Shoukry NH, Woollard DJ, Han JH, Hanson HL. 164.  et al. 2003. HCV persistence and immune evasion in the absence of memory T cell help. Science 302:659–62 [Google Scholar]
  165. Asabe S, Wieland SF, Chattopadhyay PK, Roederer M, Engle RE. 165.  et al. 2009. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J. Virol. 83:9652–62 [Google Scholar]
  166. Battegay M, Moskophidis D, Rahemtulla A, Hengartner H, Mak TW, Zinkernagel RM. 166.  1994. Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice. J. Virol. 68:4700–4 [Google Scholar]
  167. Aubert RD, Kamphorst AO, Sarkar S, Vezys V, Ha SJ. 167.  et al. 2011. Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection. PNAS 108:21182–87 [Google Scholar]
  168. Oxenius A, Zinkernagel RM, Hengartner H. 168.  1998. Comparison of activation versus induction of unresponsiveness of virus-specific CD4+ and CD8+ T cells upon acute versus persistent viral infection. Immunity 9:449–57 [Google Scholar]
  169. Penaloza-MacMaster P, Barber DL, Wherry EJ, Provine NM, Teigler JE. 169.  et al. 2015. Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection. Science 347:278–82 [Google Scholar]
  170. Waggoner SN, Cornberg M, Selin LK, Welsh RM. 170.  2012. Natural killer cells act as rheostats modulating antiviral T cells. Nature 481:394–98 [Google Scholar]
  171. Fuller MJ, Zajac AJ. 171.  2003. Ablation of CD8 and CD4 T cell responses by high viral loads. J. Immunol. 170:477–86 [Google Scholar]
  172. Brooks DG, Teyton L, Oldstone MB, McGavern DB. 172.  2005. Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. J. Virol. 79:10514–27 [Google Scholar]
  173. Kasprowicz V, Schulze Zur Wiesch J, Kuntzen T, Nolan BE, Longworth S. 173.  et al. 2008. High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcome. J. Virol. 82:3154–60 [Google Scholar]
  174. Raziorrouh B, Ulsenheimer A, Schraut W, Heeg M, Kurktschiev P. 174.  et al. 2011. Inhibitory molecules that regulate expansion and restoration of HCV-specific CD4+ T cells in patients with chronic infection. Gastroenterology 141:1422–31 [Google Scholar]
  175. Kaufmann DE, Walker BD. 175.  2009. PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J. Immunol. 182:5891–97 [Google Scholar]
  176. Kassu A, Marcus RA, D'Souza MB, Kelly-McKnight EA, Golden-Mason L. 176.  et al. 2010. Regulation of virus-specific CD4+ T cell function by multiple costimulatory receptors during chronic HIV infection. J. Immunol. 185:3007–18 [Google Scholar]
  177. Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW. 177.  et al. 2007. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat. Immunol. 8:1246–54 [Google Scholar]
  178. Ng CT, Oldstone MB. 178.  2014. IL-10: achieving balance during persistent viral infection. Curr. Top. Microbiol. Immunol. 380:129–44 [Google Scholar]
  179. Kaplan DE, Ikeda F, Li Y, Nakamoto N, Ganesan S. 179.  et al. 2008. Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis. J. Hepatol. 48:903–13 [Google Scholar]
  180. Elsaesser H, Sauer K, Brooks DG. 180.  2009. IL-21 is required to control chronic viral infection. Science 324:1569–72 [Google Scholar]
  181. Frohlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT. 181.  et al. 2009. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 324:1576–80 [Google Scholar]
  182. Schmitz I, Schneider C, Frohlich A, Frebel H, Christ D. 182.  et al. 2013. IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection. PLOS Pathog. 9:e1003362 [Google Scholar]
  183. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J. 183.  et al. 2002. A critical role for IL-21 in regulating immunoglobulin production. Science 298:1630–34 [Google Scholar]
  184. Chevalier MF, Julg B, Pyo A, Flanders M, Ranasinghe S. 184.  et al. 2011. HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function. J. Virol. 85:733–41 [Google Scholar]
  185. Feng G, Zhang JY, Zeng QL, Jin L, Fu J. 185.  et al. 2013. HCV-specific interleukin-21+CD4+ T cells responses associated with viral control through the modulation of HCV-specific CD8+ T cells function in chronic hepatitis C patients. Mol. Cells 36:362–67 [Google Scholar]
  186. Iannello A, Boulassel MR, Samarani S, Debbeche O, Tremblay C. 186.  et al. 2010. Dynamics and consequences of IL-21 production in HIV-infected individuals: a longitudinal and cross-sectional study. J. Immunol. 184:114–26 [Google Scholar]
  187. Publicover J, Goodsell A, Nishimura S, Vilarinho S, Wang ZE. 187.  et al. 2011. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J. Clin. Investig. 121:1154–62 [Google Scholar]
  188. Ren G, Esser S, Jochum C, Schlaak JF, Gerken G. 188.  et al. 2012. Interleukin 21 augments the hepatitis B virus-specific CD8+ T-cell response in vitro in patients coinfected with HIV-1. AIDS 26:2145–53 [Google Scholar]
  189. Williams LD, Bansal A, Sabbaj S, Heath SL, Song W. 189.  et al. 2011. Interleukin-21-producing HIV-1-specific CD8 T cells are preferentially seen in elite controllers. J. Virol. 85:2316–24 [Google Scholar]
  190. Yue FY, Lo C, Sakhdari A, Lee EY, Kovacs CM. 190.  et al. 2010. HIV-specific IL-21 producing CD4+ T cells are induced in acute and chronic progressive HIV infection and are associated with relative viral control. J. Immunol. 185:498–506 [Google Scholar]
  191. Harker JA, Dolgoter A, Zuniga EI. 191.  2013. Cell-intrinsic IL-27 and gp130 cytokine receptor signaling regulates virus-specific CD4+ T cell responses and viral control during chronic infection. Immunity 39:548–59 [Google Scholar]
  192. Josefowicz SZ, Lu LF, Rudensky AY. 192.  2012. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30:531–64 [Google Scholar]
  193. Iwashiro M, Messer RJ, Peterson KE, Stromnes IM, Sugie T, Hasenkrug KJ. 193.  2001. Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral infection. PNAS 98:9226–30 [Google Scholar]
  194. Kinter AL, Hennessey M, Bell A, Kern S, Lin Y. 194.  et al. 2004. CD25+CD4+ regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4+ and CD8+ HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J. Exp. Med. 200:331–43 [Google Scholar]
  195. Weiss L, Donkova-Petrini V, Caccavelli L, Balbo M, Carbonneil C, Levy Y. 195.  2004. Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood 104:3249–56 [Google Scholar]
  196. Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S. 196.  et al. 2005. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J. Virol. 79:7860–67 [Google Scholar]
  197. Punkosdy GA, Blain M, Glass DD, Lozano MM, O'Mara L. 197.  et al. 2011. Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. PNAS 108:3677–82 [Google Scholar]
  198. Sugimoto K, Ikeda F, Stadanlick J, Nunes FA, Alter HJ, Chang KM. 198.  2003. Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology 38:1437–48 [Google Scholar]
  199. Zelinskyy G, Dietze KK, Husecken YP, Schimmer S, Nair S. 199.  et al. 2009. The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response. Blood 114:3199–207 [Google Scholar]
  200. Dietze KK, Zelinskyy G, Gibbert K, Schimmer S, Francois S. 200.  et al. 2011. Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8+ T cells and reduces chronic retroviral set points. PNAS 108:2420–25 [Google Scholar]
  201. Penaloza-MacMaster P, Kamphorst AO, Wieland A, Araki K, Iyer SS. 201.  et al. 2014. Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J. Exp. Med. 211:1905–18 [Google Scholar]
  202. Eggena MP, Barugahare B, Jones N, Okello M, Mutalya S. 202.  et al. 2005. Depletion of regulatory T cells in HIV infection is associated with immune activation. J. Immunol. 174:4407–14 [Google Scholar]
  203. Oswald-Richter K, Grill SM, Shariat N, Leelawong M, Sundrud MS. 203.  et al. 2004. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells. PLOS Biol. 2:e198 [Google Scholar]
  204. Kornfeld C, Ploquin MJ, Pandrea I, Faye A, Onanga R. 204.  et al. 2005. Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS. J. Clin. Investig. 115:1082–91 [Google Scholar]
  205. MacDonald AJ, Duffy M, Brady MT, McKiernan S, Hall W. 205.  et al. 2002. CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J. Infect. Dis. 185:720–27 [Google Scholar]
  206. Medzhitov R, Schneider DS, Soares MP. 206.  2012. Disease tolerance as a defense strategy. Science 335:936–41 [Google Scholar]
  207. Crotty S. 207.  2014. T follicular helper cell differentiation, function, and roles in disease. Immunity 41:529–42 [Google Scholar]
  208. Ramiscal RR, Vinuesa CG. 208.  2013. T-cell subsets in the germinal center. Immunol. Rev. 252:146–55 [Google Scholar]
  209. Fahey LM, Wilson EB, Elsaesser H, Fistonich CD, McGavern DB, Brooks DG. 209.  2011. Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J. Exp. Med. 208:987–99 [Google Scholar]
  210. Harker JA, Lewis GM, Mack L, Zuniga EI. 210.  2011. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 334:825–29 [Google Scholar]
  211. Feng J, Hu X, Guo H, Sun X, Wang J. 211.  et al. 2012. Patients with chronic hepatitis C express a high percentage of CD4+CXCR5+ T follicular helper cells. J. Gastroenterol. 47:1048–56 [Google Scholar]
  212. Feng J, Lu L, Hua C, Qin L, Zhao P. 212.  et al. 2011. High frequency of CD4+CXCR5+ TFH cells in patients with immune-active chronic hepatitis B. PLOS ONE 6:e21698 [Google Scholar]
  213. Lindqvist M, van Lunzen J, Soghoian DZ, Kuhl BD, Ranasinghe S. 213.  et al. 2012. Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J. Clin. Investig. 122:3271–80 [Google Scholar]
  214. Petrovas C, Yamamoto T, Gerner MY, Boswell KL, Wloka K. 214.  et al. 2012. CD4 T follicular helper cell dynamics during SIV infection. J. Clin. Investig. 122:3281–94 [Google Scholar]
  215. Locci M, Havenar-Daughton C, Landais E, Wu J, Kroenke MA. 215.  et al. 2013. Human circulating PD-1+CXCR3−CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity 39:758–69 [Google Scholar]
  216. Pallikkuth S, Parmigiani A, Silva SY, George VK, Fischl M. 216.  et al. 2012. Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine. Blood 120:985–93 [Google Scholar]
  217. Cubas RA, Mudd JC, Savoye AL, Perreau M, van Grevenynghe J. 217.  et al. 2013. Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nat. Med. 19:494–99 [Google Scholar]
  218. Boswell KL, Paris R, Boritz E, Ambrozak D, Yamamoto T. 218.  et al. 2014. Loss of circulating CD4 T cells with B cell helper function during chronic HIV infection. PLOS Pathog. 10:e1003853 [Google Scholar]
  219. Planz O, Ehl S, Furrer E, Horvath E, Brundler MA. 219.  et al. 1997. A critical role for neutralizing-antibody-producing B cells, CD4+ T cells, and interferons in persistent and acute infections of mice with lymphocytic choriomeningitis virus: implications for adoptive immunotherapy of virus carriers. PNAS 94:6874–79 [Google Scholar]
  220. Thomsen AR, Johansen J, Marker O, Christensen JP. 220.  1996. Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice. J. Immunol. 157:3074–80 [Google Scholar]
  221. Hangartner L, Zellweger RM, Giobbi M, Weber J, Eschli B. 221.  et al. 2006. Nonneutralizing antibodies binding to the surface glycoprotein of lymphocytic choriomeningitis virus reduce early virus spread. J. Exp. Med. 203:2033–42 [Google Scholar]
  222. Bergthaler A, Flatz L, Verschoor A, Hegazy AN, Holdener M. 222.  et al. 2009. Impaired antibody response causes persistence of prototypic T cell-contained virus. PLOS Biol. 7:e1000080 [Google Scholar]
  223. Bukh J, Thimme R, Meunier JC, Faulk K, Spangenberg HC. 223.  et al. 2008. Previously infected chimpanzees are not consistently protected against reinfection or persistent infection after reexposure to the identical hepatitis C virus strain. J. Virol. 82:8183–95 [Google Scholar]
  224. Grady BP, Schinkel J, Thomas XV, Dalgard O. 224.  2013. Hepatitis C virus reinfection following treatment among people who use drugs. Clin. Infect. Dis. 57:Suppl. 2S105–10 [Google Scholar]
  225. Euler Z, van Gils MJ, Bunnik EM, Phung P, Schweighardt B. 225.  et al. 2010. Cross-reactive neutralizing humoral immunity does not protect from HIV type 1 disease progression. J. Infect. Dis. 201:1045–53 [Google Scholar]
  226. Wei X, Decker JM, Wang S, Hui H, Kappes JC. 226.  et al. 2003. Antibody neutralization and escape by HIV-1. Nature 422:307–12 [Google Scholar]
  227. McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF. 227.  2010. The immune response during acute HIV-1 infection: clues for vaccine development. Nat. Rev. Immunol. 10:11–23 [Google Scholar]
  228. de Jong YP, Dorner M, Mommersteeg MC, Xiao JW, Balazs AB. 228.  et al. 2014. Broadly neutralizing antibodies abrogate established hepatitis C virus infection. Sci. Transl. Med. 6:254ra129 [Google Scholar]
  229. Balazs AB, Chen J, Hong CM, Rao DS, Yang L, Baltimore D. 229.  2012. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481:81–84 [Google Scholar]
  230. Hong JJ, Amancha PK, Rogers K, Ansari AA, Villinger F. 230.  2012. Spatial alterations between CD4+ T follicular helper, B, and CD8+ T cells during simian immunodeficiency virus infection: T/B cell homeostasis, activation, and potential mechanism for viral escape. J. Immunol. 188:3247–56 [Google Scholar]
  231. Perreau M, Savoye AL, De Crignis E, Corpataux JM, Cubas R. 231.  et al. 2013. Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J. Exp. Med. 210:143–56 [Google Scholar]
  232. Hufert FT, van Lunzen J, Janossy G, Bertram S, Schmitz J. 232.  et al. 1997. Germinal centre CD4+ T cells are an important site of HIV replication in vivo. AIDS 11:849–57 [Google Scholar]
  233. Xu Y, Weatherall C, Bailey M, Alcantara S, De Rose R. 233.  et al. 2013. Simian immunodeficiency virus infects follicular helper CD4 T cells in lymphoid tissues during pathogenic infection of pigtail macaques. J. Virol. 87:3760–73 [Google Scholar]
  234. Fukazawa Y, Lum R, Okoye AA, Park H, Matsuda K. 234.  et al. 2015. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat. Med. 21:132–39 [Google Scholar]
  235. Baumjohann D, Preite S, Reboldi A, Ronchi F, Ansel KM. 235.  et al. 2013. Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype. Immunity 38:596–605 [Google Scholar]
  236. Deenick EK, Chan A, Ma CS, Gatto D, Schwartzberg PL. 236.  et al. 2010. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33:241–53 [Google Scholar]
  237. Kang SG, Liu WH, Lu P, Jin HY, Lim HW. 237.  et al. 2013. MicroRNAs of the miR-17∼92 family are critical regulators of TFH differentiation. Nat. Immunol. 14:849–57 [Google Scholar]
  238. Crawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM. 238.  et al. 2014. Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity 40:289–302 [Google Scholar]
  239. Quirion MR, Gregory GD, Umetsu SE, Winandy S, Brown MA. 239.  2009. Cutting edge: Ikaros is a regulator of Th2 cell differentiation. J. Immunol. 182:741–45 [Google Scholar]
  240. Curran MA, Geiger TL, Montalvo W, Kim M, Reiner SL. 240.  et al. 2013. Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin. J. Exp. Med. 210:743–55 [Google Scholar]
  241. Speiser DE, Utzschneider DT, Oberle SG, Munz C, Romero P, Zehn D. 241.  2014. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?. Nat. Rev. Immunol. 14:768–74 [Google Scholar]
/content/journals/10.1146/annurev-virology-100114-055226
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Innate and Adaptive Immune Regulation During Chronic Viral Infections
Annual Review of Virology 2, 573 (2015); https://doi.org/10.1146/annurev-virology-100114-055226
/content/journals/10.1146/annurev-virology-100114-055226
/content/journals/10.1146/annurev-virology-100114-055226
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  • Article Type: Review Article

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