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Role of Toll-Like Receptor (TLR) Signaling in HIV-1-Induced Adaptive Immune Activation

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Humanized Mice for HIV Research

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Abstract

Chronic immune activation has been shown to be an important driver of HIV-1 disease progression. It has been demonstrated that the humanized mouse model can be infected with HIV-1 and can lead to subsequent CD4+ T cell decline and immune activation similarly to what is observed in human chronic HIV-1 infection. Toll-like receptors (TLRs) and innate immune cells have been shown to play a pivotal role in both HIV-1 control and pathogenesis but attempts to exploit these pathways have been limited. Studies to date suggest that many of the TLR pathways are intact in the humanized mouse model, suggesting that this model can provide a useful tool to examine and manipulate the interplay between immune system and virus in efforts to control viral replication and disease. This review discusses the role of TLRs in HIV-1 infection and their expression and manipulation in the humanized mouse model.

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Abbreviations

DC:

Dendritic cells

EBV:

Epstein Barr virus

HCV:

Hepatitis C virus

HIV:

Human immunodeficiency virus

huCD34+ :

Human CD34+ hematopoietic cells

mDC:

Myeloid dendritic cells

NK:

Natural killer

NSG:

NOD/SCID/IL-2rγ−/−

pDC:

Plasmacytoid dendritic cells

TLR:

Toll-like receptor

References

  1. Giorgi JV, Hultin LE, McKeating JA, Johnson TD, Owens B, Jacobson LP, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999;179(4):859–70.

    Article  CAS  PubMed  Google Scholar 

  2. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003;187(10):1534–43.

    Article  CAS  PubMed  Google Scholar 

  3. Groux H, Torpier G, Monte D, Mouton Y, Capron A, Ameisen JC. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992;175(2):331–40.

    Article  CAS  PubMed  Google Scholar 

  4. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365–71.

    Article  CAS  PubMed  Google Scholar 

  5. Biancotto A, Grivel JC, Iglehart SJ, Vanpouille C, Lisco A, Sieg SF, et al. Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1. Blood. 2007;109(10):4272–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Gonzalez VD, Falconer K, Blom KG, Reichard O, Morn B, Laursen AL, et al. High levels of chronic immune activation in the T-cell compartments of patients coinfected with hepatitis C virus and human immunodeficiency virus type 1 and on highly active antiretroviral therapy are reverted by alpha interferon and ribavirin treatment. J Virol. 2009;83(21):11407–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, Rodriguez B, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis. 2009;199(8):1177–85 (Clinical trial Research Support, N.I.H., Extramural).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol. 2012;12(11):786–98.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Ito R, Takahashi T, Katano I, Ito M. Current advances in humanized mouse models. Cell Mol Immunol. 2012;9(3):208–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Meixlsperger S, Leung CS, Ramer PC, Pack M, Vanoaica LD, Breton G, et al. CD141+ dendritic cells produce prominent amounts of IFN-alpha after dsRNA recognition and can be targeted via DEC-205 in humanized mice. Blood. 2013;121(25):5034–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno FA, et al. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med. 2006;12(11):1316–22 (Research Support, N.I.H., Extramural).

    Article  CAS  PubMed  Google Scholar 

  12. Ye C, Choi JG, Abraham S, Wu H, Diaz D, Terreros D, et al. Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model. Proc Natl Acad Sci U S A. 2012;109(51):21052–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Tanaka S, Saito Y, Kunisawa J, Kurashima Y, Wake T, Suzuki N, et al. Development of mature and functional human myeloid subsets in hematopoietic stem cell-engrafted NOD/SCID/IL2rgammaKO mice. J Immunol. 2012;188(12):6145–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Seung E, Dudek TE, Allen TM, Freeman GJ, Luster AD, Tager AM. PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads. PLoS ONE. 2013;8(10):e77780.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Lim WH, Kireta S, Russ GR, Coates PT. Human plasmacytoid dendritic cells regulate immune responses to Epstein–Barr virus (EBV) infection and delay EBV-related mortality in humanized NOD-SCID mice. Blood. 2007;109(3):1043–50.

    Article  CAS  PubMed  Google Scholar 

  16. Hesselton RM, Greiner DL, Mordes JP, Rajan TV, Sullivan JL, Shultz LD. High levels of human peripheral blood mononuclear cell engraftment and enhanced susceptibility to human immunodeficiency virus type 1 infection in NOD/LtSz-scid/scid mice. J Infect Dis. 1995;172(4):974–82.

    Article  CAS  PubMed  Google Scholar 

  17. Lowry PA, Shultz LD, Greiner DL, Hesselton RM, Kittler EL, Tiarks CY, et al. Improved engraftment of human cord blood stem cells in NOD/LtSz-scid/scid mice after irradiation or multiple-day injections into unirradiated recipients. Biol Blood Marrow Transplant. 1996;2(1):15–23.

    CAS  PubMed  Google Scholar 

  18. Christianson SW, Greiner DL, Hesselton RA, Leif JH, Wagar EJ, Schweitzer IB, et al. Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-scid mice. J Immunol. 1997;158(8):3578–86.

    CAS  PubMed  Google Scholar 

  19. Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005;174(10):6477–89.

    Article  CAS  PubMed  Google Scholar 

  20. Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, et al. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002;100(9):3175–82.

    Article  CAS  PubMed  Google Scholar 

  21. Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti JC, Lanzavecchia A, et al. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science. 2004;304(5667):104–7.

    Article  CAS  PubMed  Google Scholar 

  22. Gimeno R, Weijer K, Voordouw A, Uittenbogaart CH, Legrand N, Alves NL, et al. Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2−/− gammac−/− mice: functional inactivation of p53 in developing T cells. Blood. 2004;104(13):3886–93.

    Article  CAS  PubMed  Google Scholar 

  23. Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988;335(6187):256–9.

    Article  CAS  PubMed  Google Scholar 

  24. McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988;241(4873):1632–9.

    Article  CAS  PubMed  Google Scholar 

  25. Lan P, Tonomura N, Shimizu A, Wang S, Yang YG. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood. 2006;108(2):487–92.

    Article  CAS  PubMed  Google Scholar 

  26. Chen Q, Khoury M, Chen J. Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice. Proc Natl Acad Sci U S A. 2009;106(51):21783–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Kwant-Mitchell A, Ashkar AA, Rosenthal KL. Mucosal innate and adaptive immune responses against herpes simplex virus type 2 in a humanized mouse model. J Virol. 2009;83(20):10664–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Strowig T, Gurer C, Ploss A, Liu YF, Arrey F, Sashihara J, et al. Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J Exp Med. 2009;206(6):1423–34.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G, et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood. 2005;106(5):1565–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Long BR, Stoddart CA. Alpha interferon and HIV infection cause activation of human T cells in NSG-BLT mice. J Virol. 2012;86(6):3327–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Brainard DM, Seung E, Frahm N, Cariappa A, Bailey CC, Hart WK, et al. Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice. J Virol. 2009;83(14):7305–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Seillet C, Laffont S, Tremollieres F, Rouquie N, Ribot C, Arnal JF, et al. The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor alpha signaling. Blood. 2012;119(2):454–64.

    Article  CAS  PubMed  Google Scholar 

  33. Chen Q, He F, Kwang J, Chan JK, Chen J. GM-CSF and IL-4 stimulate antibody responses in humanized mice by promoting T, B, and dendritic cell maturation. J Immunol. 2012;189(11):5223–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Kalberer CP, Siegler U, Wodnar-Filipowicz A. Human NK cell development in NOD/SCID mice receiving grafts of cord blood CD34+ cells. Blood. 2003;102(1):127–35.

    Article  CAS  PubMed  Google Scholar 

  35. Rajesh D, Zhou Y, Jankowska-Gan E, Roenneburg DA, Dart ML, Torrealba J, et al. Th1 and Th17 immunocompetence in humanized NOD/SCID/IL2rgammanull mice. Hum Immunol. 2010;71(6):551–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Vuckovic S, Abdul Wahid FS, Rice A, Kato M, Khalil D, Rodwell R, et al. Compartmentalization of allogeneic T-cell responses in the bone marrow and spleen of humanized NOD/SCID mice containing activated human resident myeloid dendritic cells. Exp Hematol. 2008;36(11):1496–506.

    Article  CAS  PubMed  Google Scholar 

  37. Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, et al. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med. 2009;206(1):25–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Willinger T, Rongvaux A, Takizawa H, Yancopoulos GD, Valenzuela DM, Murphy AJ, et al. Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. Proc Natl Acad Sci U S A. 2011;108(6):2390–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Rathinam C, Poueymirou WT, Rojas J, Murphy AJ, Valenzuela DM, Yancopoulos GD, et al. Efficient differentiation and function of human macrophages in humanized CSF-1 mice. Blood. 2011;118(11):3119–28.

    Article  CAS  PubMed  Google Scholar 

  40. Sato K, Misawa N, Nie C, Satou Y, Iwakiri D, Matsuoka M, et al. A novel animal model of Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis in humanized mice. Blood. 2011;117(21):5663–73.

    Article  CAS  PubMed  Google Scholar 

  41. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA, et al. A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology. 2011;140(4):1334–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Zhang L, Jiang Q, Li G, Jeffrey J, Kovalev GI, Su L. Efficient infection, activation, and impairment of pDCs in the BM and peripheral lymphoid organs during early HIV-1 infection in humanized rag2(-)/(-)gamma C(-)/(-) mice in vivo. Blood. 2011;117(23):6184–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Dudek TE, No DC, Seung E, Vrbanac VD, Fadda L, Bhoumik P, et al. Rapid evolution of HIV-1 to functional CD8+ T-cell responses in humanized BLT mice. Sci Transl Med. 2012;4(143):143ra98.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Hauber I, Hofmann-Sieber H, Chemnitz J, Dubrau D, Chusainow J, Stucka R, et al. Highly significant antiviral activity of HIV-1 LTR-specific tre-recombinase in humanized mice. PLoS Pathog. 2013;9(9):e1003587.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Meier A, Alter G, Frahm N, Sidhu H, Li B, Bagchi A, et al. MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol. 2007;81(15):8180–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Meier A, Chang JJ, Chan ES, Pollard RB, Sidhu HK, Kulkarni S, et al. Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med. 2009;15(8):955–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Beignon AS, McKenna K, Skoberne M, Manches O, DaSilva I, Kavanagh DG, et al. Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest. 2005;115(11):3265–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Lehmann C, Harper JM, Taubert D, Hartmann P, Fatkenheuer G, Jung N, et al. Increased interferon alpha expression in circulating plasmacytoid dendritic cells of HIV-1-infected patients. J Acquir Immune Defic Syndr. 2008;48(5):522–30.

    Article  CAS  PubMed  Google Scholar 

  49. Boasso A, Shearer GM. Chronic innate immune activation as a cause of HIV-1 immunopathogenesis. Clin Immunol. 2008;126(3):235–42 (Review).

    Google Scholar 

  50. Lombardi V, Van Overtvelt L, Horiot S, Moingeon P. Human dendritic cells stimulated via TLR7 and/or TLR8 induce the sequential production of Il-10, IFN-gamma, and IL-17A by naive CD4+ T cells. J Immunol. 2009;182(6):3372–9.

    Article  CAS  PubMed  Google Scholar 

  51. Agrawal S, Agrawal A, Doughty B, Gerwitz A, Blenis J, Van Dyke T, et al. Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J Immunol. 2003;171(10):4984–9.

    Article  CAS  PubMed  Google Scholar 

  52. Odorizzi PM, Wherry EJ. Immunology. An interferon paradox. Science. 2013;340(6129):155–6.

    Article  CAS  PubMed  Google Scholar 

  53. Chang JJ, Lacas A, Lindsay RJ, Doyle EH, Axten KL, Pereyra F, et al. Differential regulation of toll-like receptor pathways in acute and chronic HIV-1 infection. AIDS. 2012;26(5):533-41 (Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Mandl JN, Barry AP, Vanderford TH, Kozyr N, Chavan R, Klucking S, et al. Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med. 2008;14(10):1077–87.

    Article  CAS  PubMed  Google Scholar 

  55. Silvestri G, Sodora DL, Koup RA, Paiardini M, O’Neil SP, McClure HM, et al. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity. 2003;18(3):441–52.

    Article  CAS  PubMed  Google Scholar 

  56. Sodora DL, Allan JS, Apetrei C, Brenchley JM, Douek DC, Else JG, et al. Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts. Nat Med. 2009;15(8):861–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Harris LD, Tabb B, Sodora DL, Paiardini M, Klatt NR, Douek DC, et al. 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. 2010;84(15):7886–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Bosinger SE, Li Q, Gordon SN, Klatt NR, Duan L, Xu L, et al. Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. J Clin Invest. 2009;119(12):3556–72.

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Bosinger SE, Hosiawa KA, Cameron MJ, Persad D, Ran L, Xu L, et al. Gene expression profiling of host response in models of acute HIV infection. J Immunol. 2004;173(11):6858–63.

    Article  CAS  PubMed  Google Scholar 

  60. Chang JJ, Woods M, Lindsay RJ, Doyle EH, Griesbeck M, Chan ES, et al. Higher expression of several interferon-stimulated genes in HIV-1-infected females after adjusting for the level of viral replication. J Infect Dis. 2013;208(5):830–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Herbeuval JP, Nilsson J, Boasso A, Hardy AW, Kruhlak MJ, Anderson SA, et al. Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients. Proc Natl Acad Sci U S A. 2006;103(18):7000–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Boasso A, Herbeuval JP, Hardy AW, Anderson SA, Dolan MJ, Fuchs D, et al. HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood. 2007;109(8):3351–9 (Clinical Trial, Comparative Study Multicenter Study Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov’t).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Malleret B, Maneglier B, Karlsson I, Lebon P, Nascimbeni M, Perie L, et al. Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression. Blood. 2008;112(12):4598–608.

    Article  CAS  PubMed  Google Scholar 

  64. Manches O, Munn D, Fallahi A, Lifson J, Chaperot L, Plumas J, et al. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J Clin Invest. 2008;118(10):3431–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Chiang G, Sassaroli M, Louie M, Chen H, Stecher VJ, Sperber K. Inhibition of HIV-1 replication by hydroxychloroquine: mechanism of action and comparison with zidovudine. Clin Ther. 1996;18(6):1080-92 (Comparative Study Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.).

    Article  CAS  PubMed  Google Scholar 

  66. Naarding MA, Baan E, Pollakis G, Paxton WA. Effect of chloroquine on reducing HIV-1 replication in vitro and the DC-SIGN mediated transfer of virus to CD4+ T-lymphocytes. Retrovirology. 2007;4:6 (Research Support, Non-U.S. Gov’t).

    Article  PubMed Central  PubMed  Google Scholar 

  67. Murray SM, Down CM, Boulware DR, Stauffer WM, Cavert WP, Schacker TW, et al. Reduction of immune activation with chloroquine therapy during chronic HIV infection. J Virol. 2010;84(22):12082–6 (Randomized Controlled Trial Research Support, N.I.H., Research Support, Non-U.S. Gov’t).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Martinson JA, Montoya CJ, Usuga X, Ronquillo R, Landay AL, Desai SN. Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation. Antimicrob Agents Chemother. 2010;54(2):871–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Piconi S, Parisotto S, Rizzardini G, Passerini S, Terzi R, Argenteri B, et al. Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders. Blood. 2011;118(12):3263–72 (Research Support, Non-U.S. Gov’t).

    Article  CAS  PubMed  Google Scholar 

  70. Fredericksen BL, Wei BL, Yao J, Luo T, Garcia JV. Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus. J Virol. 2002;76(22):11440–6 (Research Support, U.S. Gov’t, P.H.S.).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Vijaykumar TS, Nath A, Chauhan A. Chloroquine mediated molecular tuning of astrocytes for enhanced permissiveness to HIV infection. Virology. 2008;381(1):1–5 (Research Support, N.I.H., Extramural).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Baenziger S, Heikenwalder M, Johansen P, Schlaepfer E, Hofer U, Miller RC, et al. Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology. Blood. 2009;113(2):377–88.

    Article  CAS  PubMed  Google Scholar 

  73. Heikenwalder M, Polymenidou M, Junt T, Sigurdson C, Wagner H, Akira S, et al. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med. 2004;10(2):187–92.

    Article  CAS  PubMed  Google Scholar 

  74. 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):7559–65.

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Cullen BR. Role and mechanism of action of the APOBEC3 family of antiretroviral resistance factors. J Virol. 2006;80(3):1067–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. 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 U S A. 2006;103(5):1440–5 (Research Support, N.I.H., Extramural).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Liu SY, Aliyari R, Chikere K, Li G, Marsden MD, Smith JK, et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity. 2013;38(1):92–105.

    Article  PubMed Central  PubMed  Google Scholar 

  78. Funderburg N, Luciano AA, Jiang W, Rodriguez B, Sieg SF, Lederman MM. Toll-like receptor ligands induce human T cell activation and death, a model for HIV pathogenesis. PLoS ONE. 2008;3(4):e1915 (Research Support, N.I.H., Extramural).

    Google Scholar 

  79. Ancuta P, Kamat A, Kunstman KJ, Kim EY, Autissier P, Wurcel A, et al. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS ONE. 2008;3(6):e2516 [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t).

    Article  PubMed Central  PubMed  Google Scholar 

  80. Balagopal A, Philp FH, Astemborski J, Block TM, Mehta A, Long R, et al. Human immunodeficiency virus-related microbial translocation and progression of hepatitis C. Gastroenterology. 2008;135(1):226–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Ogawa Y, Kawamura T, Kimura T, Ito M, Blauvelt A, Shimada S. Gram-positive bacteria enhance HIV-1 susceptibility in Langerhans cells, but not in dendritic cells, via Toll-like receptor activation. Blood. 2009;113(21):5157–66.

    Article  CAS  PubMed  Google Scholar 

  82. Thibault S, Fromentin R, Tardif MR, Tremblay MJ. TLR2 and TLR4 triggering exerts contrasting effects with regard to HIV-1 infection of human dendritic cells and subsequent virus transfer to CD4+ T cells. Retrovirology. 2009;6:42 (Research Support, Non-U.S. Gov’t).

    Article  PubMed Central  PubMed  Google Scholar 

  83. Mureith MW, Chang JJ, Lifson JD, Ndung’u T, Altfeld M. Exposure to HIV-1-encoded Toll-like receptor 8 ligands enhances monocyte response to microbial encoded Toll-like receptor 2/4 ligands. AIDS. 2010;24(12):1841–8 (Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Nordone SK, Ignacio GA, Su L, Sempowski GD, Golenbock DT, Li L, et al. Failure of TLR4-driven NF-kappa B activation to stimulate virus replication in models of HIV type 1 activation. AIDS Res Hum Retroviruses. 2007;23(11):1387–95.

    Article  CAS  PubMed  Google Scholar 

  85. Heggelund L, Muller F, Lien E, Yndestad A, Ueland T, Kristiansen KI, et al. Increased expression of toll-like receptor 2 on monocytes in HIV infection: possible roles in inflammation and viral replication. Clin Infect Dis. 2004;39(2):264–9.

    Article  CAS  PubMed  Google Scholar 

  86. Song Y, Zhuang Y, Zhai S, Huang D, Zhang Y, Kang W, et al. Increased expression of TLR7 in CD8(+) T cells leads to TLR7-mediated activation and accessory cell-dependent IFN-gamma production in HIV type 1 infection. AIDS Res Hum Retroviruses. 2009;25(12):1287–95.

    Article  CAS  PubMed  Google Scholar 

  87. Lester RT, Yao XD, Ball TB, McKinnon LR, Kaul R, Wachihi C, et al. Toll-like receptor expression and responsiveness are increased in viraemic HIV-1 infection. AIDS. 2008;22(6):685–94.

    Article  CAS  PubMed  Google Scholar 

  88. Spranger S, Frankenberger B, Schendel DJ. NOD/scid IL-2Rg(null) mice: a preclinical model system to evaluate human dendritic cell-based vaccine strategies in vivo. J Transl Med. 2012;10:30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Cravens PD, Melkus MW, Padgett-Thomas A, Islas-Ohlmayer M, Del PMM, Garcia JV. Development and activation of human dendritic cells in vivo in a xenograft model of human hematopoiesis. Stem Cells. 2005;23(2):264–78.

    Article  PubMed  Google Scholar 

  90. Hofer U, Schlaepfer E, Baenziger S, Nischang M, Regenass S, Schwendener R, et al. Inadequate clearance of translocated bacterial products in HIV-infected humanized mice. PLoS Pathog. 2010;6(4):e1000867.

    Article  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Harvard Medical School, Boston, MA, USA

    J. Judy Chang PhD & Marcus Altfeld

  2. Department of Infectious Diseases, Monash University, Level 7, The Alfred Centre, 99 Commercial Road, 3004, Melbourne, VIC, Australia

    J. Judy Chang PhD

  3. Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany

    Marcus Altfeld

Authors
  1. J. Judy Chang PhD
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  2. Marcus Altfeld
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Correspondence to J. Judy Chang PhD .

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Editors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Larisa Y. Poluektova

  2. Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    J. Victor Garcia

  3. Research Center for AIDS Laboratory of Viral Pathogenesis, Kyoto University Institute for Virus Research, Sakyo-ku, Japan

    Yoshio Koyanagi

  4. Division of Hematology, University Hospital Zürich, Zürich, Switzerland

    Markus G. Manz

  5. Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA

    Andrew M. Tager

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Chang, J., Altfeld, M. (2014). Role of Toll-Like Receptor (TLR) Signaling in HIV-1-Induced Adaptive Immune Activation. In: Poluektova, L., Garcia, J., Koyanagi, Y., Manz, M., Tager, A. (eds) Humanized Mice for HIV Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1655-9_23

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