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Inhibition of human immunodeficiency virus-1 (HIV-1) replication after
transduction of granulocyte colony-stimulating factor-mobilized CD34+ cells
from HIV-1-infected donors using retroviral vectors containing anti-HIV-1
genes
G Bauer, P Valdez, K Kearns, I Bahner, SF Wen, JA Zaia and DB Kohn
Department of Pediatrics, University of Southern California School of
Medicine, Los Angeles, USA.
Transfer of "anti-HIV-1 genes" into hematopoietic stem cells of human
immunodeficiency virus-1 (HIV-1)-infected individuals may be a potent
therapeutic approach to render mature cells arising from transduced stem
cells resistant to the destructive events associated with HIV-1 infection.
To determine the feasibility of gene therapy for acquired immunodeficiency
syndrome in individuals already infected with HIV-1, granulocyte
colony-stimulating factor mobilized peripheral blood CD34+ cells were
isolated from HIV-1-infected individuals and transduced with retroviral
vectors containing three different anti-HIV-1-genes: the Rev binding domain
of the Rev Responsive Element (RRE decoy) (L-RRE-neo), a double hammerhead
ribozyme vector targeted to cleave the tat and rev transcripts
(L-TR/TAT-neo), and the trans-dominant mutant of rev (M10) (L-M10-SN). As a
control, a vector mediating only neomycin resistance (LN) was used. After 3
days of transduction on allogeneic stroma in the presence of stem cell
factor, interleukin-6 (IL-6), and IL-3, the cultures were G418-selected,
and then challenged with HIV-1(JR-FL) and a primary HIV-1 isolate. Compared
with the control cultures, the L-RRE- neo-, L-TR/TAT-neo-, and
L-M10-SN-transduced cultures displayed up to 1,000-fold inhibition of HIV-1
replication after challenge with HIV- 1(JR-FL) and the primary HIV-1
isolate. Growth of the hematopoietic cells in long-term bone marrow culture
was not perturbed by the presence of any of the anti-HIV-1 genes. This
study shows that anti-HIV- 1 genes can be introduced into CD34+ cells from
individuals already infected with HIV-1, and strongly inhibit HIV-1
replication in primary monocytes derived from the CD34+ progenitors.
Volume 89,
Issue 7,
pp. 2259-2267,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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