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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2342-2350
GENE THERAPY
Efficient gene transfer into human primary blood lymphocytes by
surface-engineered lentiviral vectors that display a T
cell-activating polypeptide
Marielle Maurice,
Els Verhoeyen,
Patrick Salmon,
Didier Trono,
Stephen J. Russell, and
François-Loïc Cosset
From the Laboratoire Vectorologie Rétrovirale et
Thérapie Génique, Unité de Virologie Humaine, U412
INSERM, IFR 74 and ENS de Lyon, France; Department of Genetics and
Microbiology, Faculty of Medicine, University of Geneva, Geneva,
Switzerland; and the Molecular Medicine Program, Mayo Clinic,
Rochester, Minnesota.
In contrast to oncoretroviruses, lentiviruses such as human
immunodeficiency virus 1 (HIV-1) are able to integrate their genetic material into the genome of nonproliferating cells that are
metabolically active. Likewise, vectors derived from HIV-1 can
transduce many types of nonproliferating cells, with the exception of
some particular quiescent cell types such as resting T cells.
Completion of reverse transcription, nuclear import, and subsequent
integration of the lentivirus genome do not occur in these cells unless
they are activated via the T-cell receptor (TCR) or by cytokines or
both. However, to preserve the functional properties of these important gene therapy target cells, only minimal activation with cytokines or
TCR-specific antibodies should be performed during gene transfer. Here
we report the characterization of HIV-1-derived lentiviral vectors
whose virion surface was genetically engineered to display a T
cell-activating single-chain antibody polypeptide derived from the
anti-CD3 OKT3 monoclonal antibody. Interaction of OKT3 IgGs with the
TCR can activate resting peripheral blood lymphocytes (PBLs) by
promoting the transition from G0 to G1 phases
of the cell cycle. Compared to unmodified HIV-1-based vectors,
OKT3-displaying lentiviral vectors strongly increased gene delivery in
freshly isolated PBLs by up to 100-fold. Up to 48% transduction could be obtained without addition of PBL activation stimuli during infection. Taken together, these results show that surface-engineered lentiviral vectors significantly improve transduction of primary lymphocytes by activating the target cells. Moreover these results provide a proof of concept for an approach that may have utility in
various gene transfer applications, including in vivo gene delivery.
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