Hiller C, Tamgüney G, Stolte N, Mätz-Rensing K, Lorenzen D, Hör S, Thurau M, Wittmann S, Slavin S, Fickenscher H
Institut für Klinische und Molekulare Virologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schlossgarten 4, Erlangen, D-91054, Germany.
Virology. 2000 Dec 20;278(2):445-55. doi: 10.1006/viro.2000.0665.
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.
猴疱疹病毒可作为人类T淋巴细胞的高效基因表达载体，因此可能在实验性白血病治疗中得到应用。我们构建了重组病毒，用于功能性表达单纯疱疹病毒1型（HSV）的胸苷激酶（TK）作为自杀基因。在给予更昔洛韦后，这些病毒在体外可靠地实现了对转导的非许可性人类T细胞的靶向清除。为了在最严格的许可条件下测试该功能的可靠性，在本研究中，我们分析了更昔洛韦和阿昔洛韦这两种前体药物对普通狨猴中由野生型猴疱疹病毒C488或表达HSV TK的重组衍生物诱导的急性白血病发生的影响。抗病毒药物治疗并未影响急性疾病的快速发展。相反，HSV tk基因的存在导致疾病进展更快。此外，在低血清浓度的培养条件下，表达HSV TK的病毒比野生型病毒显示出更快的复制速度。因此，HSV TK加速了猴疱疹病毒的复制并增强了其致病性。当HSV TK作为转基因应用于具有复制能力的DNA病毒载体进行基因治疗时，应普遍考虑这一点。
