Herpesvirus saimiri pathogenicity enhanced by thymidine kinase of herpes simplex virus.
Herpesvirus saimiri can be used as an efficient gene expression vector for human T lymphocytes and thus may allow applications in experimental leukemia therapy. We constructed recombinant viruses for the functional expression of the thymidine kinase (TK) of herpes simplex virus type 1 (HSV) as a suicide gene. These viruses reliably allowed the targeted elimination of transduced nonpermissive human T cells in vitro after the administration of ganciclovir. To test the reliability of this function under the most stringent permissive conditions, in this study we analyzed the influence of the prodrugs ganciclovir and acyclovir in common marmosets on the acute leukemogenesis induced by either wild-type herpesvirus saimiri C488 or by a recombinant derivative expressing TK of HSV. Antiviral drug treatment did not influence the rapid development of acute disease. In contrast, the presence of the HSV tk gene resulted in a faster disease progression. In addition, HSV TK-expressing viruses showed faster replication than wild-type virus in culture at low serum concentrations. Thus, HSV TK accelerates the replication of herpesvirus saimiri and enhances its pathogenicity. This should be generally considered when HSV TK is applied as a transgene in replication-competent DNA virus vectors for gene therapy.
Hiller
C
C
Institut für Klinische und Molekulare Virologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schlossgarten 4, Erlangen, D-91054, Germany.
Tamgüney
G
G
Stolte
N
N
Mätz-Rensing
K
K
Lorenzen
D
D
Hör
S
S
Thurau
M
M
Wittmann
S
S
Slavin
S
S
Fickenscher
H
H
D000212:Acyclovir / Q000494:pharmacology; D000818:Animals; D002144:Callithrix; D002460:Cell Line; D002478:Cells, Cultured; D015774:Ganciclovir / Q000494:pharmacology; D005822:Genetic Vectors; D006561:Herpes Simplex / Q000473:pathology*; D006801:Humans; D015458:Leukemia, T-Cell / Q000473:pathology / Q000503:physiopathology*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity*; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
D013937:Thymidine Kinase; D015774:Ganciclovir; D000212:Acyclovir