Ex vivo selection and expansion of cells based on expression of a mutated inosine monophosphate dehydrogenase 2 after HIV vector transduction: effects on lymphocytes, monocytes, and CD34+ stem cells

Molecular Therapy : the Journal of the American Society of Gene Therapy
Priscilla YamJiing-Kuan Yee

Abstract

Hematopoietic progenitor cells (HPCs) represent an ideal target for gene therapy treatment of human immunodeficiency virus (HIV) infection. However, gene delivery into quiescent HPCs by retroviral or lentiviral vectors remains relatively poor. We evaluated a selection scheme based on the expression of a variant of inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme in the de novo purine biosynthesis pathway. As lymphocytes depend more than other cell types on de novo synthesis of purines, IMPDH inhibitors such as mycophenolic acid (MPA) can selectively expand lymphocytes overexpressing the enzymes. We used HIV vectors to deliver an IMPDH variant into T cells and HPCs. We showed that the transduced T cells became resistant to MPA selection. By expressing a short hairpin RNA gene targeted to the HIV gag transcript, the MPA-selected T cells became resistant to HIV-1 infection. Monocyte/macrophages derived from the transduced HPCs differentiated normally and exhibited normal function as measured by B7 up-regulation and phagocytosis when stimulated. Our results suggest that this system may be applicable as a selection strategy to enrich transduced T lymphocytes and mononuclear cells in vivo for HIV gene therapy.

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Citations

Apr 17, 2008·Cancer Research·Harjeet SinghLaurence J N Cooper
Nov 30, 2011·Human Gene Therapy·Anne-Marie W TurnerKevin V Morris
Jan 4, 2012·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Qiuwei PanLuc J W van der Laan
Jun 18, 2014·British Journal of Haematology·Waseem Qasim, Adrian J Thrasher
Apr 5, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Joseph AndersonRamesh Akkina
May 11, 2021·Clinical & Translational Immunology·Carmen Alvarez-FernándezJavier Briones

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