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Novel humanized murine models for HIV research

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Abstract

There are few models in which HIV pathogenesis, particularly gut-associated lymphoid tissue CD4+ T-cell depletion, can be studied and in which potential clinical interventions against HIV disease can be evaluated. HIV cannot be studied in normal mice due to the limited species tropism of the virus. Through the pioneering efforts of many investigators, humanized mice are now routinely used to rapidly advance HIV research. It is important to recognize that not all humanized murine models are equal, and their strengths and weaknesses must be taken into consideration to obtain information that is most relevant to the human condition. This review distinguishes the major humanization protocols and highlights each model’s recent contributions to HIV research, including mucosal transmission, gut-associated lymphoid tissue pathogenesis, and the evaluation of novel therapeutic and prevention approaches to potentially treat HIV disease and prevent the further spread of AIDS.

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References and Recommended Reading

  1. Mosier DE, Gulizia RJ, Baird SM, Wilson DB: Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 1988, 335:256–259.

    Article  PubMed  CAS  Google Scholar 

  2. Baumann JG, Unutmaz D, Miller MD, et al.: Murine T cells potently restrict human immunodeficiency virus infection. J Virol 2004, 78:12537–12547.

    Article  PubMed  CAS  Google Scholar 

  3. McCune J, Kaneshima H, Krowka J, et al.: The SCID-hu mouse: a small animal model for HIV infection and pathogenesis. Annu Rev Immunol 1991, 9:399–429.

    Article  PubMed  CAS  Google Scholar 

  4. McCune JM, Kaneshima H, Lieberman M, et al.: The SCID-hu mouse: current status and potential applications. Curr Top Microbiol Immunol 1989, 152:183–193.

    PubMed  CAS  Google Scholar 

  5. Brenchley JM, Price DA, Douek DC: HIV disease: fallout from a mucosal catastrophe? Nat Immunol 2006, 7:235–239.

    Article  PubMed  CAS  Google Scholar 

  6. Dandekar S: Pathogenesis of HIV in the gastrointestinal tract. Curr HIV/AIDS Rep 2007, 4:10–15.

    Article  PubMed  Google Scholar 

  7. Shultz LD, Ishikawa F, Greiner DL: Humanized mice in translational biomedical research. Nat Rev Immunol 2007, 7:118–130.

    Article  PubMed  CAS  Google Scholar 

  8. Garcia S, Dadaglio G, Gougeon ML: Limits of the human-PBL-SCID mice model: severe restriction of the V beta T-cell repertoire of engrafted human T cells. Blood 1997, 89:329–336.

    PubMed  CAS  Google Scholar 

  9. Saxon A, Macy E, Denis K, et al.: Limited B cell repertoire in severe combined immunodeficient mice engrafted with peripheral blood mononuclear cells derived from immunodeficient or normal humans. J Clin Invest 1991, 87:658–665.

    Article  PubMed  CAS  Google Scholar 

  10. McCune JM, Namikawa R, Kaneshima H, et al.: The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science 1988, 241:1632–1639.

    Article  PubMed  CAS  Google Scholar 

  11. D’Cruz OJ, Uckun FM: Limitations of the human-PBLSCID mouse model for vaginal transmission of HIV-1. Am J Reprod Immunol 2007, 57:353–360.

    Article  PubMed  CAS  Google Scholar 

  12. Di Fabio S, Van Roey J, Giannini G, et al.: Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation. AIDS 2003, 17:1597–1604.

    Article  PubMed  Google Scholar 

  13. Khanna KV, Whaley KJ, Zeitlin L, et al.: Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent. J Clin Invest 2002, 109:205–211.

    PubMed  CAS  Google Scholar 

  14. Lederman MM, Offord RE, Hartley O: Microbicides and other topical strategies to prevent vaginal transmission of HIV. Nat Rev Immunol 2006, 6:371–382.

    Article  PubMed  CAS  Google Scholar 

  15. Su L, Kaneshima H, Bonyhadi M, et al.: HIV-1-induced thymocyte depletion is associated with indirect cytopathogenicity and infection of progenitor cells in vivo. Immunity 1995, 2:25–36.

    Article  PubMed  CAS  Google Scholar 

  16. Stoddart CA, Bales CA, Bare JC, et al.: Validation of the SCID-hu thy/liv mouse model with four classes of licensed antiretrovirals. PLoS ONE 2007, 2:e655.

    Article  PubMed  Google Scholar 

  17. Traggiai E, Chicha L, Mazzucchelli L, et al.: Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 2004, 304:104–107.

    Article  PubMed  CAS  Google Scholar 

  18. Manz MG: Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity 2007, 26:537–541.

    Article  PubMed  CAS  Google Scholar 

  19. Berges BK, Wheat WH, Palmer BE, et al.: HIV-1 infection and CD4 T cell depletion in the humanized Rag2-/-gamma c-/- (RAG-hu) mouse model. Retrovirology 2006, 3:76.

    Article  PubMed  Google Scholar 

  20. Ter Brake O, Legrand N, von Eije KJ, et al.: Evaluation of safety and efficacy of RNAi against HIV-1 in the human immune system (Rag-2(-/-)(c)(-/-)) mouse model. Gene Ther 2008 Jul 31 (Epub ahead of print).

  21. Van Duyne R, Cardenas J, Easley R, et al.: Effect of transcription peptide inhibitors on HIV-1 replication. Virology 2008, 376:308–322.

    Article  PubMed  Google Scholar 

  22. An DS, Poon B, Ho Tsong, et al.: Use of a novel chimeric mouse model with a functionally active human immune system to study human immunodeficiency virus type 1 infection. Clin Vaccine Immunol 2007, 14:391–396.

    Article  PubMed  CAS  Google Scholar 

  23. Baenziger S, Tussiwand R, Schlaepfer E, et al.: Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-gamma c-/- mice. Proc Natl Acad Sci U S A 2006, 103:15951–15956.

    Article  PubMed  CAS  Google Scholar 

  24. Berges BK, Akkina SR, Folkvord JM, et al.: Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag2-/- gamma c -/- (RAG-hu) mice. Virology 2008, 373:342–351.

    Article  PubMed  CAS  Google Scholar 

  25. Gorantla S, Sneller H, Walters L, et al.: Human immunodeficiency virus type 1 pathobiology studied in humanized BALB/c-Rag2-/-gammac-/- mice. J Virol 2007, 81:2700–2712.

    Article  PubMed  CAS  Google Scholar 

  26. Jiang Q, Zhang L, Wang R, et al.: FoxP3+CD4+ regulatory T cells play an important role in acute HIV-1 infection in humanized Rag2-/-gammaC-/- mice in vivo. Blood 2008, 112:2858–2868.

    Article  PubMed  CAS  Google Scholar 

  27. Zhang L, Kovalev GI, Su L: HIV-1 infection and pathogenesis in a novel humanized mouse model. Blood 2007, 109:2978–2981.

    PubMed  CAS  Google Scholar 

  28. Hiramatsu H, Nishikomori R, Heike T, et al.: Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/gammcnull mice model. Blood 2003, 102:873–880.

    Article  PubMed  CAS  Google Scholar 

  29. Ishikawa F, Yasukawa M, Lyons B, et al.: Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood 2005, 106:1565–1573.

    Article  PubMed  CAS  Google Scholar 

  30. Watanabe S, Ohta S, Yajima M, et al.: Humanized NOD/SCID/IL2R {gamma}null mice transplanted with hematopoietic stem cells under nonmyeloablative conditions show prolonged life spans and allow detailed analysis of human immunodeficiency virus type 1 pathogenesis. J Virol 2007, 81:13259–13264.

    Article  PubMed  CAS  Google Scholar 

  31. Watanabe S, Terashima K, Ohta S, et al.: Hematopoietic stem cell-engrafted NOD/SCID/IL2Rgamma null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses. Blood 2007, 109:212–218.

    Article  PubMed  CAS  Google Scholar 

  32. Kumar P, Ban HS, Kim SS, et al.: T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell 2008, 134:577–586.

    Article  PubMed  CAS  Google Scholar 

  33. Melkus MW, Estes JD, Padgett-Thomas A, et al.: Humanized mice mount specific adaptive and innate immune response to EBV and TSST-1. Nat Med 2006, 12:1316–1322.

    Article  PubMed  CAS  Google Scholar 

  34. Wege AK, Melkus MW, Denton PW, et al.: Functional and phenotypic characterization of the humanized BLT mouse model. Curr Top Microbiol Immunol 2008, 324:149–165.

    Article  PubMed  CAS  Google Scholar 

  35. Tonomura N, Habiro K, Shimizu A, et al.: Antigen-specific human T-cell responses and T cell-dependent production of human antibodies in a humanized mouse model. Blood 2008, 111:4293–4296.

    Article  PubMed  CAS  Google Scholar 

  36. Lan P, Tonomura N, Shimizu A, et al.: Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood 2006, 108:487–492.

    Article  PubMed  CAS  Google Scholar 

  37. Tonomura N, Shimizu A, Wang S, et al.: Pig islet xenograft rejection in a mouse model with an established human immune system. Xenotransplantation 2008, 15:129–135.

    Article  PubMed  Google Scholar 

  38. Makida R, Hofer MF, Takase K, et al.: Bacterial superantigens induce V beta-specific T cell receptor internalization. Mol Immunol 1996, 33:891–900.

    Article  PubMed  CAS  Google Scholar 

  39. Sun Z, Denton PW, Estes JD, et al.: Intrarectal transmission, systemic infection and CD4+ T cell depletion in humanized mice infected with HIV-1. J Exp Med 2007, 204:705–714.

    Article  PubMed  CAS  Google Scholar 

  40. Hofer U, Baenziger S, Heikenwalder M, et al.: RAG2-/- gamma(c)-/- mice transplanted with CD34+ cells from human cord blood show low levels of intestinal engraftment and are resistant to rectal transmission of human immunodeficiency virus. J Virol 2008, 82:12145–12153.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  42. Bell SJ, Rigby R, English N, et al.: Migration and maturation of human colonic dendritic cells. J Immunol 2001, 166:4958–4967.

    PubMed  CAS  Google Scholar 

  43. Abuzakouk M, Carton J, Feighery C, et al.: CD4+ CD8+ and CD8alpha+ beta-T lymphocytes in human small intestinal lamina propria. Eur J Gastroenterol Hepatol 1998, 10:325–329.

    Article  PubMed  CAS  Google Scholar 

  44. Carton J, Byrne B, Madrigal-Estebas L, et al.: CD4+CD8+ human small intestinal T cells are decreased in coeliac patients, with CD8 expression downregulated on intraepithelial T cells in the active disease. Eur J Gastroenterol Hepatol 2004, 16:961–968.

    Article  PubMed  Google Scholar 

  45. Lynch S, Kelleher D, Feighery C, et al.: Flow cytometric analysis of intraepithelial lymphocytes from human small intestinal biopsies reveals populations of CD4+CD8+ and CD8[alpha][alpha]+ cells. Eur J Gastroenterol Hepatol 1993, 5:907–912.

    Article  Google Scholar 

  46. Denton PW, Estes JD, Sun Z, et al.: Antiretroviral preexposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med 2008, 5:e16.

    Article  PubMed  Google Scholar 

  47. Foster JL, Garcia JV: Role of Nef in HIV-1 replication and pathogenesis. Adv Pharmacol 2007, 55:389–409.

    Article  PubMed  CAS  Google Scholar 

  48. De Boer RJ: Understanding the failure of CD8+ T-cell vaccination against simian/human immunodeficiency virus. J Virol 2007, 81:2838–2848.

    Article  PubMed  Google Scholar 

  49. Koff WC, Johnson PR, Watkins DI, et al.: HIV vaccine design: insights from live attenuated SIV vaccines. Nat Immunol 2006, 7:19–23.

    Article  PubMed  CAS  Google Scholar 

  50. McMichael AJ, Hanke T: HIV vaccines 1983–2003. Nat Med 2003, 9:874–880.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Room Y9.206, Dallas, TX, 75390-9113, USA

    Paul W. Denton & J. Victor Garcia

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  1. Paul W. Denton
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  2. J. Victor Garcia
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Correspondence to J. Victor Garcia.

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Denton, P.W., Garcia, J.V. Novel humanized murine models for HIV research. Curr HIV/AIDS Rep 6, 13–19 (2009). https://doi.org/10.1007/s11904-009-0003-2

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