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Blood, 1 August 2002, Vol. 100, No. 3, pp. 813-822
GENE THERAPY
Lentiviral vectors containing the human immunodeficiency virus
type-1 central polypurine tract can efficiently transduce
nondividing hepatocytes and antigen-presenting cells in
vivo
Thierry VandenDriessche,
Lieven Thorrez,
Luigi Naldini,
Antonia Follenzi,
Lieve Moons,
Zwi Berneman,
Desire Collen, and
Marinee K. L. Chuah
From the Center for Transgene Technology and Gene
Therapy, Flanders Interuniversity Institute for
Biotechnology-University of Leuven, Belgium; Laboratory for Gene
Transfer and Therapy, IRCC, Institute for Cancer Research and
Treatment, University of Turin Medical School, Candiolo, Italy;
Laboratory of Experimental Hematology, Antwerp University Hospital,
University of Antwerp, Belgium.
High-titer self-inactivating human immunodeficiency virus type-1
(HIV-1)-based vectors expressing the green fluorescent protein reporter gene that contained the central polypurine and termination tract and the woodchuck hepatitis virus posttranscriptional regulatory element were constructed. Transduction efficiency and
biodistribution were determined, following systemic administration of
these improved lentiviral vectors. In adult severe combined
immunodeficiency (SCID) mice, efficient stable gene transfer was
achieved in the liver (8.0% ± 6.0%) and spleen
(24% ± 3%). Most transduced hepatocytes and nonhepatocytes were
nondividing, thereby obviating the need to induce liver cell
proliferation. In vivo gene transfer with this improved lentiviral
vector was relatively safe since liver enzyme concentration in the
plasma was only moderately and transiently elevated. In addition,
nondividing major histocompatibility complex class II-positive splenic
antigen-presenting cells (APCs) were efficiently transduced in SCID and
normal mice. Furthermore, B cells were efficiently transduced, whereas
T cells were refractory to lentiviral transduction in vivo. However, in
neonatal recipients, lentiviral transduction was more widespread and
included not only hepatocytes and splenic APCs but also cardiomyocytes.
The present study suggests potential uses of improved lentiviral
vectors for gene therapy of genetic blood disorders resulting from
serum protein deficiencies, such as hemophilia, and hepatic disease.
However, the use of liver-specific promoters may be warranted to
circumvent inadvertent transgene expression in APCs. In addition, these
improved lentiviral vectors could potentially be useful for genetic
vaccination and treatment of perinatal cardiac disorders.
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