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Zinc Finger Nuclease Editing of Hematopoietic Stem Cells as an Anti-HIV Therapy

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Humanized Mice for HIV Research

Abstract

Hematopoietic stem cell (HSC) transplanted humanized mice are a valuable small animal model for preclinical testing of HSC-based gene therapies, since the engraftment and subsequent differentiation of the cells in the mice allows a rigorous assessment of whether the genetic manipulation in any way impacts HSC function. In addition, since the HSC give rise to human CD4+ T cells, the mice can support an HIV-1 infection. This means that the mice are particularly suited to the evaluation of anti-HIV gene therapies, where the actual target human cell and gene therapy reagents can be evaluated in a system that supports infection by the authentic human virus. In this chapter we review the role played by humanized mouse models in the preclinical development of a promising anti-HIV approach based on disruption of the human CCR5 gene in human HSC, using zinc finger nuclease editing.

Kathleen A. Burke is deceased.

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References

  1. Shultz LD, et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hematopoietic stem cells. J Immunol. 2005;174:6477–89.

    Article  CAS  PubMed  Google Scholar 

  2. Ishikawa F, et al. Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice. Blood. 2005;106:1565–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Wu L, et al. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature. 1996;384:179–83.

    Article  CAS  PubMed  Google Scholar 

  4. Samson M, et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature. 1996;382:722–5.

    Article  CAS  PubMed  Google Scholar 

  5. Wood A, Armour D. The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS. In: King FD, Lawton G, editors. Prog Med Chem; 2005;43:239–71.

    Google Scholar 

  6. Shimizu S, et al. A highly efficient short hairpin RNA potently down-regulates CCR5 expression in systemic lymphoid organs in the hu-BLT mouse model. Blood. 2010;115:1534–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Allers K, et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood. 2010;117:2791–99.

    Article  PubMed  Google Scholar 

  8. Hütter G, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360:692–8.

    Article  PubMed  Google Scholar 

  9. Yukl SA, et al. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog. 2013;9:e1003347.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Cannon P, June C. Chemokine receptor 5 knockout strategies. Curr Opin HIV AIDS. 2011;6:74–9.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Gaj T, et al. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 2013;31:397–405.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Perez EE, et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008;26:808–16.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Shaykhmetov DM, et al. Efficient gene transfer into human CD34+ cells by retargeted adenovirus vector. J Virol. 2000;74:2567–83.

    Article  Google Scholar 

  14. Holt N, et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol. 2010;28:839–47.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Joglekar AV, et al. Integrase-defective lentiviral vectors as a delivery platform for targeted modification of the adenosine deaminase locus. Mol Ther. 2013;21:1705–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Lei Y, et al. Gene editing of human embryonic stem cells via an engineered baculoviral vector carrying zinc-finger nucleases. Mol Ther. 2011;19:942–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Li H, et al. In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature. 2011;475:217–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Lombardo A, et al. Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat Biotechnol. 2007;25:1298–306.

    Article  CAS  PubMed  Google Scholar 

  19. Li L, et al. Genomic editing of the HIV co-receptor CCR5 in adult hematopoietic stem and progenitor cells using zinc finger nucleases. Mol Ther. 2013;21:1259–69.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Körbling M, Anderlini P. Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood. 2001;98:2900–08.

    Article  PubMed  Google Scholar 

  21. Sica S, et al. G-CSF and peripheral blood progenitor cells. Lancet. 1992;339:1411.

    Article  CAS  PubMed  Google Scholar 

  22. Cannon PM, et al. Electroporation of ZFN mRNA enables efficient CCR5 gene disruption in mobilized blood hematopoietic stem cells at clinical scale. Mol Ther. 2013;21:S71–S2.

    Google Scholar 

  23. Traggiai E, et al. Development of a human adaptive immuse system in cord blood cell-transplanted mice. Science. 2004;304:104–7.

    Article  CAS  PubMed  Google Scholar 

  24. Baenziger S, 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;103:15951–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Watanabe S, et al. Hematopoietic stem cell-engrafted NOD/SCID/IL2Rγnull mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses. Blood. 2007;109:212–8.

    Article  CAS  PubMed  Google Scholar 

  26. Berges B, et al. HIV-1 infection and CD4 T cell depletion in the humanized Rag2-/-γc-/- (RAG-hu) mouse model. Retrovirology. 2006;3:76.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Nie C, et al. Selective infection of CD4+ effector memory T lymphocytes leads to preferential depletion of memory T lymphocytes in R5 HIV-1-infected humanized NOD/SCID/IL2-Rγnullmice. Virology. 2009;394:64–72.

    Article  CAS  PubMed  Google Scholar 

  28. McCune J, et al. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988;241:1632–9.

    Article  CAS  PubMed  Google Scholar 

  29. Melkus MW, et al. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med. 2006;12:1316–22.

    Article  CAS  PubMed  Google Scholar 

  30. Billerbeck E, et al. Development of human CD4+ FoxP3+ regulatory T cells in human stem cell factor–, granulocyte-macrophage colony-stimulating factor–, and interleukin-3–expressing NOD-SCID IL2Rγnull humanized mice. Blood. 2011;117(11):3076–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Brehm MA. Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rγ null mice is enhanced by transgenic expression of membrane-bound human SCF. Blood. 2012;119:2778–88.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Rongvaux A, et al. Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo. Proc Natl Acad Sci U S A. 2011;108:2378–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Shultz LD, et al. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2rγnull humanized mice. Proc Natl Acad Sci U S A. 2010;107:13022–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Strowig T, et al. Transgenic expression of human signal regulatory protein alpha in Rag2-/-γc -/- mice improves engraftment of human hematopoietic cells in humanized mice. Proc Natl Acad Sci U S A. 2011;108:13218–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Anderson J, et al. Safety and efficacy of a lentiviral vector containing three anti-HIV genes- CCR5 ribozyme, Tat-rev siRNA, and TAR decoy-in SCID-hu mouse-derived T cells. Mol Ther. 2007;15:1182–8.

    Article  CAS  PubMed  Google Scholar 

  36. Hauber I, et al. Highly significant antiviral activity of HIV-1 LTR-specific Tre-recombinase in humanized mice. PLoS Pathog. 2013;9:e1003587.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Joseph A, et al. Inhibition of in vivo HIV infection in humanized mice by gene therapy of human hematopoietic stem cells with a lentiviral vector encoding a broadly neutralizing anti-HIV antibody. J Virol. 2010;84:6645–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Kitchen SG, et al. In vivo suppression of HIV by antigen specific T cells derived from engineered hematopoietic stem cells. PLoS Pathog. 2012;8:e1002649.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Walker JE, et al. Generation of an HIV-1 resistant immune system with CD34+ hematopoietic stem cells transduced with a triple-combination anti-HIV lentiviral vector. J Virol. 2012;86:5719–29.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Tebas P, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370:901–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Maier DA, et al. Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5. Hum Gene Ther. 2013;24:245–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Wilen CB, et al. Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. PLoS Pathog. 2011;7:e1002020.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Yuan J, et al. Zinc-finger nuclease editing of human CXCR4 promotes HIV-1 CD4+ T cell resistance and enrichment. Mol Ther. 2012;20:849–59.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Hofer U, et al. Pre-clinical modeling of CCR5 knockout in human hematopoietic stem cells by zinc finger nucleases using humanized mice. J Infect Dis. 2013;208:S160–4.

    Article  Google Scholar 

  45. Tricot G, et al. Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients. Blood. 1995;85:588–96.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Institutes of Health research grant HL073104 and the California HIV/AIDS Research Program (CHRP) grant ID12-USC-245 the James B. Pendleton Charitable Trust. CE was supported by a fellowship from the CHRP, F10-USC-207, UH was supported by a fellowship from the Swiss National Science Foundation, and OM was supported by a fellowship from the California Institute for Regenerative Medicine. The article is dedicated to the memory of our friend and colleague, Kathy Burke.

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Authors and Affiliations

  1. University of Southern California, Los Angeles, CA, USA

    Nathalia G. Holt, Colin M. Exline, Orla Mulhern, Ursula Hofer, Kathleen A. Burke & Jill E. Oldenburg

  2. Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, HMR502, 90033, Los Angeles, CA, USA

    Paula M. Cannon

Authors
  1. Nathalia G. Holt
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  2. Colin M. Exline
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  3. Orla Mulhern
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  4. Ursula Hofer
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  5. Kathleen A. Burke
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  6. Jill E. Oldenburg
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  7. Paula M. Cannon
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Corresponding author

Correspondence to Paula M. Cannon .

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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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Holt, N. et al. (2014). Zinc Finger Nuclease Editing of Hematopoietic Stem Cells as an Anti-HIV Therapy. 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_32

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