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Journal of Virology, April 2001, p. 3547-3555, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3547-3555.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Lentivirus Vector-Mediated Hematopoietic Stem Cell Gene Transfer of Common Gamma-Chain Cytokine Receptor in Rhesus Macaques

Dong Sung An,1 Sam K. P. Kung,1 Aylin Bonifacino,2 Robert P. Wersto,2 Mark E. Metzger,2 Brian A. Agricola,2 Si Hua Mao,1 Irvin S. Y. Chen,1,* and Robert E. Donahue2

UCLA AIDS Institute and Department of Microbiology and Immunology and Molecular Genetics and Department of Medicine, Los Angeles, California 90095,1 and Hematology Branch, National Heart, Lung, and Blood Institute, Rockville, Maryland 208502

Received 16 August 2000/Accepted 16 January 2001

Nonhuman primate model systems of autologous CD34+ cell transplant are the most effective means to assess the safety and capabilities of lentivirus vectors. Toward this end, we tested the efficiency of marking, gene expression, and transplant of bone marrow and peripheral blood CD34+ cells using a self-inactivating lentivirus vector (CS-Rh-MLV-E) bearing an internal murine leukemia virus long terminal repeat derived from a murine retrovirus adapted to replicate in rhesus macaques. In vitro cytokine stimulation was not required to achieve efficient transduction of CD34+ cells resulting in marking and gene expression of the reporter gene encoding enhanced green fluorescent protein (EGFP) following transplant of the CD34+ cells. Monkeys transplanted with mobilized peripheral blood CD34+ cells resulted in EGFP expression in 1 to 10% of multilineage peripheral blood cells, including red blood cells and platelets, stable for 15 months to date. The relative level of gene expression utilizing this vector is 2- to 10-fold greater than that utilizing a non-self-inactivating lentivirus vector bearing the cytomegalovirus immediate-early promoter. In contrast, in animals transplanted with autologous bone marrow CD34+ cells, multilineage EGFP expression was evident initially but diminished over time. We further tested our lentivirus vector system by demonstrating gene transfer of the human common gamma-chain cytokine receptor gene (gamma c), deficient in X-linked SCID patients and recently successfully used to treat disease. Marking was 0.42 and .001 HIV-1 vector DNA copy per 100 cells in two animals. To date, all EGFP- and gamma c-transplanted animals are healthy. This system may prove useful for expression of therapeutic genes in human hematopoietic cells.

* Corresponding author. Mailing address: UCLA School of Medicine, 10833 LeConte Ave., 11-934 Factor Bldg., Los Angeles, CA 90095. Phone: (310) 825-4793. Fax: (310) 794-7682. E-mail: rtaweesu{at}ucla.edu.

Journal of Virology, April 2001, p. 3547-3555, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3547-3555.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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