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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-02-0578.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3416-3423
GENE THERAPY
Specific transgene expression in human and mouse CD4+
cells using lentiviral vectors with regulatory sequences from the
CD4 gene
Gilles Marodon,
Enguerran Mouly,
Emma J. Blair,
Charlotte Frisen,
François M. Lemoine, and
David Klatzmann
From the Centre National de la Recherche Scientifique
(CNRS) UMR-7087, Biologie et Thérapeutique des Pathologies
Immunitaires, Centre d'Etude et de Recherche en Virologie et en
Immunologie (CERVI), Hôpital La
Pitié-Sâlpétrière, Paris,
France.
Achieving cell-specific expression of a therapeutic transgene by
gene transfer vectors represents a major goal for gene therapy. To
achieve specific expression of a transgene in CD4+ cells,
we have generated lentiviral vectors expressing the enhanced green
fluorescent protein (eGFP) reporter gene
under the control of regulatory sequences derived from the
CD4 gene a minimal promoter and the proximal enhancer,
with or without the silencer. Both lentiviral vectors could be produced
at high titers (more than 107 infectious particles per
milliliter) and were used to transduce healthy murine hematopoietic
stem cells (HSCs). On reconstitution of RAG-2-deficient mice with
transduced HSCs, the specific vectors were efficiently expressed in T
cells, minimally expressed in B cells, and not expressed in immature
cells of the bone marrow. Addition of the CD4
gene-silencing element in the vector regulatory sequences led to
further restriction of eGFP expression into CD4+ T cells in
reconstituted mice and in ex vivo-transduced human T cells. Non-T
CD4+ dendritic and macrophage cells derived from human
CD34+ cells in vitro expressed the transgene of the
specific vectors, albeit at lower levels than CD4+ T cells.
Altogether, we have generated lentiviral vectors that allow specific
targeting of transgene expression to CD4+ cells after
differentiation of transduced mice HSCs and human mature T cells.
Ultimately, these vectors may prove useful for in situ injections for
in vivo gene therapy of HIV infection or genetic immunodeficiencies.
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