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J Virol, June 1998, p. 4882-4892, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
High-Efficiency Gene Transfer into Normal and
Adenosine Deaminase-Deficient T Lymphocytes Is Mediated by
Transduction on Recombinant Fibronectin Fragments
Karen E.
Pollok,1
Helmut
Hanenberg,1
Timothy W.
Noblitt,1
Wendy L.
Schroeder,1
Ikunoshin
Kato,2
David
Emanuel,1 and
David A.
Williams1,3,*
Section of Pediatric Hematology/Oncology,
Herman B. Wells Center for Pediatric Research, Riley Hospital for
Children,1 and
Howard Hughes Medical
Institute,3 Indiana University School of
Medicine, Indianapolis, Indiana 46202-5525, and
Biotechnology Research Laboratories, Takara Shuzo Company,
Otsu, Shiga 520-21, Japan2
Received 15 December 1997/Accepted 11 March 1998
Primary human T lymphocytes are powerful targets for genetic
modification, although the use of these targets in human gene therapy protocols has been hampered by low levels of transduction. We
have shown previously that significant increases in the
transduction of hematopoietic stem and progenitor cells with retroviral
vectors can be obtained by the colocalization of the retrovirus and
target cells on specific fibronectin (FN) adhesion domains (H. Hanenberg, X. L. Xiao, D. Dilloo, K. Hashino, I. Kato, and D. A. Williams, Nat. Med. 2:876-882, 1996). We studied the transfer of
genes into primary T lymphocytes by using FN-assisted retroviral gene
transfer. Activated T lymphocytes were infected for three consecutive
days on the recombinant FN fragment CH-296 with a retroviral
vector encoding the murine B7-1 protein. Transduced lymphocytes
were analyzed for murine B7-1 expression, and it was found that
under optimal conditions, 80 to 89% of the CD3+
lymphocytes were transduced. Gene transfer was predominantly augmented
by the interaction between VLA-4 on the T lymphocytes and the FN
adhesion site CS-1. Adenosine deaminase (ADA)-deficient primary T
lymphocytes transduced on CH-296 with a retrovirus encoding murine ADA (mADA) exhibited levels of mADA activity severalfold higher
than the levels of the endogenous human ADA protein observed in normal
human T lymphocytes. Strikingly, the long-term expression of the
transgene was dependent on the activation status of the lymphocytes.
This approach will have important applications in human gene therapy
protocols targeting primary T lymphocytes.
*
Corresponding author. Mailing address: Herman B. Wells
Center for Pediatric Research, 1044 W. Walnut St., Room 402, Indianapolis, IN 46202. Phone: (317) 274-8679. Fax: (317)
274-8679. E-mail: dwilliam{at}indyvax.iupui.edu.
J Virol, June 1998, p. 4882-4892, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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