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Blood, 1 January 2001, Vol. 97, No. 1, pp. 122-129
GENE THERAPY
Molecular mechanism for ganciclovir resistance in human T
lymphocytes transduced with retroviral vectors carrying the herpes
simplex virus thymidine kinase gene
Marina I. Garin,
Elaine Garrett,
Pierre Tiberghien,
Jane F. Apperley,
David Chalmers,
Junia V. Melo, and
Christophe Ferrand
From the Department of Haematology, Imperial College
School of Medicine, Hammersmith Hospital, London, United Kingdom;
and the Laboratoire de Thérapeutique Immuno-Moléculaire,
Etablissement Français du Sang-Bourgogne/ Franche-Comté,
Besançon, France.
The herpes simplex virus thymidine kinase gene type 1 (HSV-Tk) ganciclovir (GCV) system is a novel therapeutic
strategy for the modulation of graft-versus-host disease (GVHD), a
major complication of allogeneic stem cell transplantation (allo-SCT).
Retroviral-mediated gene transfer of the HSV-Tk gene into
donor T lymphocytes before allo-SCT may allow their in vivo selective
depletion after treatment with GCV. The expression of the
HSV-Tk gene was analyzed in vitro in CEM cells, a human
lymphoblastoid cell line, transduced with 2 different vectors, each
containing the HSV-Tk gene and a selectable marker gene.
GCV-resistant clones were identified within the clones expressing the
marker gene. Characterization of the molecular events leading to this
resistance revealed a 227-bp deletion in the HSV-Tk gene
due to the presence of cryptic splice donor and acceptor sites within
the HSV-Tk gene sequence. Furthermore, it was confirmed
that this deletion was present in human primary T cells transduced with
either vector and in 12 patients who received transduced donor T cells,
together with a T-cell-depleted allo-SCT. In vivo circulating
transduced T cells containing the truncated HSV-Tk gene
were identified in all patients immediately after infusion and up to
800 days after transplantation. In patients who received GCV as
treatment for GVHD, a progressive increase in the proportion of
transduced donor T cells carrying the deleted HSV-Tk
gene was observed. These results suggest that the limitations within
the HSV-Tk/GCV system can be improved by developing
optimized retroviral vectors to ensure maximal killing of
HSV-Tk-transduced cells.
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