Assessment of Herpesvirus saimiri as a potential human gene therapy vector

Stevenson, Alexander J.; Cooper, Matthew A.; Griffiths, Joanne C.; Gibson, Paul C.; Whitehouse, Adrian; Jones, Elena F.; Markham, Alexander F.; Kinsey, Sally; Meredith, David M.

doi:10.1002/(sici)1096-9071(199903)57:3<269::aid-jmv10>3.0.co;2-8

Cited by 28 publications

(29 citation statements)

References 22 publications

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“…Although we have previously demonstrated low levels of virus production at early times after infection in a wide variety of human cell lines transduced with HVS, 36 we were unable to detect any evidence of lytic virus growth in persistently infected Jurkat cells using a sensitive virus recovery assay. In addition, no transcripts of an abundant IE gene could be detected in the cell.…”

Section: Discussioncontrasting

confidence: 76%

A herpesvirus saimiri-based gene therapy vector with potential for use in cancer immunotherapy

et al. 2000

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The herpesvirus saimiri (HVS) genome has the capacity to incorporate large amounts of heterologous DNA and can be maintained episomally in many different human cell types. To evaluate the efficacy of HVS-mediated gene transfer into human hemopoietic cells, we investigated the ability of an HVS-based construct, carrying the enhanced green fluorescent protein (EGFP) and neomycin resistance genes, to transduce a variety of human hemopoietic cell lines and primary CD34 ϩ cells. As measured by flow cytometry, the numbers of EGFP ϩ cells at 2 days postinfection differed between various cell types ranging, from 1.3% for KG1 cells to 56.8% for THP-1 cells. In addition, the expression of EGFP in Jurkat cells was retained at Ͼ95% per round of cell division over a period of 6 weeks (comparable with Epstein-Barr virus-derived gene therapy systems). Although the virus was not specifically disabled, no lytic viral mRNAs could be detected in transduced Jurkat cells, and infectious virus could not be detected by sensitive virus recovery assay. We also describe a simple centrifugation method that increases the efficiency of transduction by Ͼ100% in some cases and may be generally applicable to other herpesvirus-based vectors for ex vivo gene delivery. Using this technique, we were able to demonstrate a tropism for CD34 ϩ /CD14 ϩ cells, transducing 30% of the population. These cells are known to give rise to dendritic cells (the most potent of the antigen-presenting cells), suggesting that the vector could be used to deliver DNA sequences encoding tumor antigens for cancer immunotherapy.

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Section: Discussioncontrasting

confidence: 76%

A herpesvirus saimiri-based gene therapy vector with potential for use in cancer immunotherapy

et al. 2000

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“…We and others have previously demonstrated that HVS can infect a wide range of human cell lines and that the HVS genome persists in a latent episomal state that segregates to progeny upon cell division allowing longterm in vitro gene expression. [7][8][9][10][11] More recently, we demonstrated that the HVS genome can persist in human tumor xenografts derived from ex vivo HVS-infected human carcinoma cells. 12,19 Our previous work has demonstrated that HVS-based vectors (expressing GFP) persisted as nonintegrated episomes in vivo, and provided long-term transgene expression with no evidence of promoter silencing, viral spread or cytopathic effects.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 More recently, HVS recombinants have been produced expressing beta-galactosidase or enhanced green fluorescence protein (EGFP), and the neomycin resistance genes under the control of the IE CMV and SV40 promoters, respectively. [8][9][10] Analysis using these viruses, which can be grown to a high titer in the permissive owl monkey kidney (OMK) cell line, has demonstrated infection of a wide variety of human carcinoma cell lines at approaching 100% efficiency.…”

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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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“…This analysis was performed on COS-7 cells infected with HVS strain A-11. COS-7 cells were used because of their ease of culture and because they are fully permissive for HVS infection (Stevenson et al, 1999). COS-7 cells were infected with HVS for 24 h at an m.o.i.…”

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The gene product encoded by ORF 57 of herpesvirus saimiri regulates the redistribution of the splicing factor SC-35.

Cooper

Goodwin

Hall

et al. 1999

Journal of General Virology

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The herpesvirus saimiri (HVS) gene product encoded by ORF 57 shares limited C-terminal similarity with herpes simplex virus 1 ICP27, a protein that has been demonstrated to be involved in the inhibition of host-cell splicing and is responsible for the redistribution of components of the spliceosome. It has previously been shown that ORF 57 can either activate or repress viral gene expression by a post-transcriptional mechanism. Furthermore, repression of gene expression by ORF 57 is dependent on the presence of an intron within the target gene coding region. In this report, it is shown that HVS infection results in the redistribution of the SC-35 splicing factor in the infected cell nucleus. Furthermore, the redistributed SC-35 colocalized with the ORF 57 protein product and expression of the protein alone was sufficient to cause the redistribution of the spliceosome components. These results suggest that the mechanism by which ORF 57 downregulates expression of intron-containing genes involves the redistribution of the spliceosome complex.

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Assessment of Herpesvirus saimiri as a potential human gene therapy vector

Cited by 28 publications

References 22 publications

A herpesvirus saimiri-based gene therapy vector with potential for use in cancer immunotherapy

A herpesvirus saimiri-based gene therapy vector with potential for use in cancer immunotherapy

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

The gene product encoded by ORF 57 of herpesvirus saimiri regulates the redistribution of the splicing factor SC-35.

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