Modeling Anti-HIV-1 HSPC-Based Gene Therapy in Humanized Mice Previously Infected with HIV-1.

Journal: Molecular therapy. Methods & clinical development
Published Date: Dec 1, 2017

Abstract

Investigations of anti-HIV-1 human hematopoietic stem/progenitor cell (HSPC)-based gene therapy have been performed by HIV-1 challenge after the engraftment of gene-modified HSPCs in humanized mouse models. However, the clinical application of gene therapy is to treat HIV-1-infected patients. Here, we developed a new method to investigate an anti-HIV-1 HSPC-based gene therapy in humanized mice previously infected with HIV-1. First, humanized mice were infected with HIV-1. When plasma viremia reached >10 copies/mL 3 weeks after HIV-1 infection, the mice were myeloablated with busulfan and transplanted with anti-HIV-1 gene-modified CD34 HSPCs transduced with a lentiviral vector expressing two short hairpin RNAs (shRNAs) against CCR5 and HIV-1 long terminal repeat (LTR), along with human thymus tissue under the kidney capsule. Anti-HIV-1 vector-modified human CD34 HSPCs successfully repopulated peripheral blood and lymphoid tissues in HIV-1 previously infected humanized mice. Anti-HIV-1 shRNA vector-modified CD4 T lymphocytes showed selective advantage in HIV-1 previously infected humanized mice. This new method will be useful for investigations of anti-HIV-1 gene therapy when testing in a more clinically relevant experimental setting.

Authors

  • Wannisa Khamaikawin
    School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Saki Shimizu
    Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • Masakazu Kamata
    Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • Ruth Cortado
    School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Yujin Jung
    School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Jennifer Lam
    School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Jing Wen
    Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Patrick Kim
    Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • Yiming Xie
    Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Sanggu Kim
    Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Hubert Arokium
    Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Angela P Presson
    Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Irvin S Y Chen
    Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • Dong Sung An
    Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

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