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Hematopoietic stem cell-based gene therapy for acquired immunodeficiency
syndrome: efficient transduction and expression of RevM10 in myeloid cells
in vivo and in vitro
L Su, R Lee, M Bonyhadi, H Matsuzaki, S Forestell, S Escaich, E Bohnlein and H Kaneshima
Progenesys Program, SyStemix, Inc, Palo Alto, CA 94304, USA.
Gene delivery via the hematopoietic stem cell (HSC) offers an attractive
means to introduce antiviral genes into both T cells and macrophages for
acquired immunodeficiency syndrome (AIDS) gene therapy. An amphotropic
retroviral vector encoding a bicistronic gene coexpressing RevM10 and the
murine CD8alpha' chain (lyt2) was developed to transduce HSC/progenitor
cells. After transduction of CD34+ cells isolated from human umbilical cord
blood, the lyt2 molecule detected by flow cytometry was used to monitor the
level of gene transduction and expression and to enrich RevM10-expressing
cells by cell sorting without drug selection. Using this quantitative
method, high levels of gene transduction and expression (around 20%) were
achieved by high- speed centrifugation of CD34+ cells with the retroviral
supernatant (spinoculation). After reconstitution of human bone marrow
implanted in SCID mice (SCID-hu bone) with the transduced HSC/progenitor
cells, a significant number of donor-derived CD14+ bone marrow cells were
found to express the RevM10/lyt2 gene. Finally, replication of a
macrophage- tropic human immunodeficiency virus-type 1 (HIV-1) isolate was
greatly inhibited in the lyt2+/CD14+ cells differentiated from transduced
CD34+ cells after the enrichment of lyt2+ population. Thus, the RevM10 gene
did not appear to inhibit the differentiation of HSC/progneitor cells into
monocytes/macrophages. The level of retrovirus-mediated RevM10 expression
in monocytes/macrophages derived from transduced HSCs is sufficient to
suppress HIV-1 replication.
Volume 89,
Issue 7,
pp. 2283-2290,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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