Engineering Cellular Resistance to HIV-1 Infection In Vivo Using a Dual Therapeutic Lentiviral Vector

Bryan P Burke; Bernard R Levin; Jane Zhang; Anna Sahakyan; Joshua Boyer; Maria V Carroll; Joanna Camba Colón; Naomi Keech; Valerie Rezek; Gregory Bristol; Erica Eggers; Ruth Cortado; Maureen P Boyd; Helen Impey; Saki Shimizu; Emily L Lowe; Gene-Errol E Ringpis; Sohn G Kim; Dimitrios N Vatakis; Louis R Breton; Jeffrey S Bartlett; Irvin S Y Chen; Scott G Kitchen; Dong Sung An; Geoff P Symonds

doi:10.1038/mtna.2015.10

Molecular Therapy: Nucleic Acids (Jan 2015)

Engineering Cellular Resistance to HIV-1 Infection In Vivo Using a Dual Therapeutic Lentiviral Vector

Bryan P Burke,
Bernard R Levin,
Jane Zhang,
Anna Sahakyan,
Joshua Boyer,
Maria V Carroll,
Joanna Camba Colón,
Naomi Keech,
Valerie Rezek,
Gregory Bristol,
Erica Eggers,
Ruth Cortado,
Maureen P Boyd,
Helen Impey,
Saki Shimizu,
Emily L Lowe,
Gene-Errol E Ringpis,
Sohn G Kim,
Dimitrios N Vatakis,
Louis R Breton,
Jeffrey S Bartlett,
Irvin S Y Chen,
Scott G Kitchen,
Dong Sung An,
Geoff P Symonds

Affiliations

Bryan P Burke: Calimmune, Inc., Los Angeles, California, USA
Bernard R Levin: Division of Hematology–Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Jane Zhang: Calimmune, Inc., Los Angeles, California, USA
Anna Sahakyan: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA
Joshua Boyer: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA
Maria V Carroll: Calimmune, Inc., Los Angeles, California, USA
Joanna Camba Colón: Calimmune, Inc., Los Angeles, California, USA
Naomi Keech: Calimmune, Inc., Los Angeles, California, USA
Valerie Rezek: Division of Hematology–Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Gregory Bristol: Division of Hematology–Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Erica Eggers: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA
Ruth Cortado: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA
Maureen P Boyd: Calimmune, Inc., Los Angeles, California, USA
Helen Impey: Calimmune, Inc., Los Angeles, California, USA
Saki Shimizu: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA
Emily L Lowe: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA
Gene-Errol E Ringpis: Calimmune, Inc., Los Angeles, California, USA
Sohn G Kim: Division of Hematology–Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Dimitrios N Vatakis: Division of Hematology–Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Louis R Breton: Calimmune, Inc., Los Angeles, California, USA
Jeffrey S Bartlett: Calimmune, Inc., Los Angeles, California, USA
Irvin S Y Chen: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Scott G Kitchen: Division of Hematology–Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA
Dong Sung An: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA
Geoff P Symonds: Calimmune, Inc., Los Angeles, California, USA

DOI: https://doi.org/10.1038/mtna.2015.10
Journal volume & issue: Vol. 4, no. C

Abstract

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We described earlier a dual-combination anti-HIV type 1 (HIV-1) lentiviral vector (LVsh5/C46) that downregulates CCR5 expression of transduced cells via RNAi and inhibits HIV-1 fusion via cell surface expression of cell membrane-anchored C46 antiviral peptide. This combinatorial approach has two points of inhibition for R5-tropic HIV-1 and is also active against X4-tropic HIV-1. Here, we utilize the humanized bone marrow, liver, thymus (BLT) mouse model to characterize the in vivo efficacy of LVsh5/C46 (Cal-1) vector to engineer cellular resistance to HIV-1 pathogenesis. Human CD34+ hematopoietic stem/progenitor cells (HSPC) either nonmodified or transduced with LVsh5/C46 vector were transplanted to generate control and treatment groups, respectively. Control and experimental groups displayed similar engraftment and multilineage hematopoietic differentiation that included robust CD4+ T-cell development. Splenocytes isolated from the treatment group were resistant to both R5- and X4-tropic HIV-1 during ex vivo challenge experiments. Treatment group animals challenged with R5-tropic HIV-1 displayed significant protection of CD4+ T-cells and reduced viral load within peripheral blood and lymphoid tissues up to 14 weeks postinfection. Gene-marking and transgene expression were confirmed stable at 26 weeks post-transplantation. These data strongly support the use of LVsh5/C46 lentiviral vector in gene and cell therapeutic applications for inhibition of HIV-1 infection.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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