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Blood, 15 November 2000, Vol. 96, No. 10, pp. 3385-3391
GENE THERAPY
Lentivirus-based vectors transduce mouse hematopoietic stem cells
with similar efficiency to Moloney murine leukemia
virus-based vectors
Stephane Barrette,
Janet L. Douglas,
Nancy E. Seidel, and
David M. Bodine
From the Hematopoiesis Section, Genetics and Molecular
Biology Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda, MD; and Systemix, Palo Alto, CA.
The low levels of transduction of human hematopoietic stem cells
(HSCs) with Moloney murine leukemia virus (MLV) vectors have been an obstacle to gene therapy for hematopoietic diseases. It has
been demonstrated that lentivirus vectors are more efficient than MLV
vectors at transducing nondividing cell lines as well as human
CD34+ cells and severe combined immunodeficiency disease
repopulating cells. We compared transduction of cell lines and
Lin bone marrow cells, using a vesicular stomatitis virus
G (VSV-G)-pseudotyped lentivirus or MLV vectors carrying a green
fluorescent protein marker gene. As predicted, the lentivirus
vector was more efficient at transducing mouse and human
growth-inhibited cell lines. The transduction of mouse HSC by
lentivirus vectors was compared directly to MLV vectors in a
co-transduction assay. In this assay, transduction by ecotropic MLV is
a positive internal control for downstream steps in retrovirus
transduction, including cell division. Both the VSV-G lentivirus and
MLV vectors transduced mouse HSCs maintained in cytokine-free medium at
very low frequency, as did the ecotropic control. The lentivirus vector
and the MLV vector were equally efficient at transducing bone
marrow HSCs cultured in interleukin 3 (IL-3), IL-6, and stem cell
factor for 96 hours. In conclusion, although lentivirus vectors
are able to transduce growth-inhibited cell lines, the cell cycle
status of HSCs render them resistant to lentivirus-mediated
transduction, and it is hypothesized that entry into cycle, not
necessarily division, may be a requirement for efficient
lentivirus-mediated transduction.
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