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

Wannisa Khamaikawin; Saki Shimizu; Masakazu Kamata; Ruth Cortado; Yujin Jung; Jennifer Lam; Jing Wen; Patrick Kim; Yiming Xie; Sanggu Kim; Hubert Arokium; Angela P. Presson; Irvin S.Y. Chen; Dong Sung An

Molecular Therapy: Methods & Clinical Development (Jun 2018)

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

Wannisa Khamaikawin,
Saki Shimizu,
Masakazu Kamata,
Ruth Cortado,
Yujin Jung,
Jennifer Lam,
Jing Wen,
Patrick Kim,
Yiming Xie,
Sanggu Kim,
Hubert Arokium,
Angela P. Presson,
Irvin S.Y. Chen,
Dong Sung An

Affiliations

Wannisa Khamaikawin: School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, Los Angeles, CA 90095, USA
Saki Shimizu: Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, 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; UCLA AIDS Institute, Los Angeles, CA 90095, USA
Yujin Jung: School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, Los Angeles, CA 90095, USA
Jennifer Lam: School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, Los Angeles, CA 90095, USA
Jing Wen: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, Los Angeles, CA 90095, USA
Patrick Kim: Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, Los Angeles, CA 90095, USA
Yiming Xie: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, Los Angeles, CA 90095, USA
Sanggu Kim: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, Los Angeles, CA 90095, USA
Hubert Arokium: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, Los Angeles, CA 90095, USA
Angela P. Presson: Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Epidemiology, University of Utah, Salt Lake City, UT 84132, USA
Irvin S.Y. Chen: Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, Los Angeles, CA 90095, USA
Dong Sung An: Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; School of Nursing, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, Los Angeles, CA 90095, USA; Corresponding author: Dong Sung An, School of Nursing, University of California, Los Angeles, 188 BSRB, 615 Charles E. Young Dr. South, Los Angeles, CA 90095, USA.

Journal volume & issue: Vol. 9
pp. 23 – 32

Abstract

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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 >107 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. Keywords: humanized mouse model, gene therapy for HIV/AIDS, HPSC-based gene therapy

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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