Functional long-term thymidine kinase suicide gene expression in human T cells using a herpesvirus saimiri vector

Hiller, Christian; Wittmann, Sabine; Slavin, Shimon; Fickenscher, Helmut

doi:10.1038/sj.gt.3301158

Cited by 26 publications

(42 citation statements)

References 70 publications

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“…Moreover, the ability of HVS to infect and transform human T cells has led to the development of HVS as a potential episomal vector for adoptive immunotherapy of infectious and malignant diseases. [15][16][17][18] To improve the biological safety of HVSbased vectors, the prodrug activating HSV thymidine kinase (HSV-TK) gene has been inserted into the HVS genome by homologous recombination. 15,16 This allows the efficient elimination of both macaque and human T cells previously infected and transformed with the HVS-TK virus, in the presence of low concentrations of gancyclovir.…”

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confidence: 99%

“…[15][16][17][18] To improve the biological safety of HVSbased vectors, the prodrug activating HSV thymidine kinase (HSV-TK) gene has been inserted into the HVS genome by homologous recombination. 15,16 This allows the efficient elimination of both macaque and human T cells previously infected and transformed with the HVS-TK virus, in the presence of low concentrations of gancyclovir. The reinfusion of large numbers of autologous HVS-TK-transformed macaque T cells in the Old World primate was well tolerated and persisted for extended periods of time.…”

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confidence: 99%

“…Therefore, this HVS-based elimination method may form the basis of a novel method for the T-cell-dependent immunotherapy of resistant residual leukemia while avoiding the risk of uncontrolled graft versus host disease. [15][16][17] A prerequisite for the further development of HVS as a cancer gene delivery vector has been to elucidate whether HVS can maintain the properties of high infectivity rates and episomal persistence observed in vitro in an in vivo environment. To this end, tumor xenograft experiments were performed in nude mice comparing uninfected or HVS-infected human carcinoma cell lines.…”

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confidence: 99%

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Efficient infection and persistence of a herpesvirus saimiri-based gene delivery vector into human tumor xenografts and multicellular spheroid cultures

et al. 2004

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Herpesvirus saimiri (HVS) has the ability to infect a variety of human cell lines and establish a persistent infection by virtue of episomal maintenance. Moreover, the viral episome provides sustained expression of a heterologous transgene. HVS-based vectors can also persist for a long term in tumor xenografts generated from HVS-infected human carcinoma cell lines. The viral episome remains latent within the xenograft allowing long-term transgene expression. These properties, in addition to its ability to incorporate large amounts of heterologous DNA, make HVS an attractive potential gene delivery vector. Here we report on the further evaluation of such HVS-based vectors. We demonstrate for the first time that HVS can efficiently infect solid tumor xenografts derived from a variety of human carcinoma cells via direct intratumoral injections. Furthermore, HVS can efficiently infect spheroid cultures, a three-dimensional cell culture system that closely resembles a tumor. Upon infection of both the tumor xenografts and spheroid cultures, HVS-based vectors can establish a persistent episomal infection within the tumor xenograft allowing expression of a heterologous transgene. These results suggest that HVS-based vectors may be suitable for cancer gene therapy applications.

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confidence: 99%

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confidence: 99%

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Efficient infection and persistence of a herpesvirus saimiri-based gene delivery vector into human tumor xenografts and multicellular spheroid cultures

et al. 2004

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“…22 Moreover, they retain most of the parental T-cell properties, such as surface phenotype, major histocompatibility complex-restricted antigen recognition, interleukin-2 (IL-2)-dependent growth and early signal transduction events, suggesting the possible use of HVS as T-cell vectors for heterologous gene expression. 14,[23][24][25] By rhadinoviral vector-mediated transduction of primary T cells, we achieved efficient long-term expression of the suicide gene thymidine kinase and the targeted elimination of transduced T cells upon low doses of ganciclovir. 23 Consistent with these results, the reinfusion of transduced autologous T cells in macaques was well tolerated without the occurrence of lymphoproliferative disease.…”

Section: Introductionmentioning

confidence: 99%

“…14,[23][24][25] By rhadinoviral vector-mediated transduction of primary T cells, we achieved efficient long-term expression of the suicide gene thymidine kinase and the targeted elimination of transduced T cells upon low doses of ganciclovir. 23 Consistent with these results, the reinfusion of transduced autologous T cells in macaques was well tolerated without the occurrence of lymphoproliferative disease. 26 In addition to T-cell applications, HVS vectors have been suggested for various other applications.…”

Section: Introductionmentioning

confidence: 99%

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

2010

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The rhadinovirus herpesvirus saimiri (HVS) as a gene delivery vector allows large DNA insertions and long-termed gene expression. In the case of T-cell transduction, such vectors use the viral transformation-associated genes of HVS C488 for T-cell amplification. In this report, we investigated whether the gene for the catalytic telomerase subunit human telomerase reverse transcriptase (hTERT) can substitute for the transformation-associated genes in rhadinoviral T-cell transduction and amplification. By using virus mutants generated by en passant mutagenesis from bacterial artificial chromosomes, we observed a very early and functional transgene expression even by virus mutants without transformation-associated genes. The markers of T-cell transformation by HVS, namely CD2 hyperreactivity, overexpression of interleukin-26, and of the tyrosine kinase Lyn could neither be induced nor enhanced by ectopic hTERT expression. When the viral transformation-associated genes were replaced by the hTERT gene, it was not sufficient for growth transformation, although hTERT was efficiently transduced and functionally expressed by the rhadinovirus vector. Thus, the transformation-associated proteins StpC and Tip are responsible for the T-cell phenotype after transduction by HVS and, additionally, modulate telomerase activity independently of hTERT expression.

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Cell transformation byHerpesvirus saimiri

Tsygankov

2004

Journal Cellular Physiology

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Herpesvirus saimiri (Saimiriine herpesvirus-2), a g2-herpesvirus (rhadinovirus) of non-human primates, causes T-lymphoproliferative diseases in susceptible organisms and transforms human and non-human T lymphocytes to continuous growth in vitro in the absence of stimulation. T cells transformed by H. saimiri retain many characteristics of intact T lymphocytes, such as the sensitivity to interleukin-2 and the ability to recognize the corresponding antigens. As a result, H. saimiri is widely used in immunobiology for immortalization of various difficult-to-obtain and/or -to-maintain T cells in order to obtain useful experimental models. In particular, H. saimiri-transformed human T cells are highly susceptible to infection with HIV-1 and -2. This makes them a convenient tool for propagation of poorly replicating strains of HIV, including primary clinical isolates. Therefore, the mechanisms mediating transformation of T cells by H. saimiri are of considerable interest. A single transformation-associated protein, StpA or StpB, mediates cell transformation by H. saimiri strains of group A or B, respectively. Strains of group C, which exhibit the highest oncogenic potential, have two proteins involved in transformation-StpC and Tip. Both proteins have been shown to dramatically affect signal transduction pathways leading to the activation of crucial transcription factors. This review is focused on the biological effects and molecular mechanisms of action of proteins involved in H. saimiri-dependent transformation.

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Functional long-term thymidine kinase suicide gene expression in human T cells using a herpesvirus saimiri vector

Cited by 26 publications

References 70 publications

Efficient infection and persistence of a herpesvirus saimiri-based gene delivery vector into human tumor xenografts and multicellular spheroid cultures

Efficient infection and persistence of a herpesvirus saimiri-based gene delivery vector into human tumor xenografts and multicellular spheroid cultures

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

Cell transformation byHerpesvirus saimiri

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