Abstract:
:The oncolytic herpes simplex virus (HSV) that has been approved for clinical practice and those HSVs in clinical trials are attenuated viruses, often with the neurovirulence gene γ134.5 and additional genes deleted. One strategy to engineer nonattenuated oncolytic HSVs consists of retargeting the viral tropism to a cancer-specific receptor of choice, exemplified by HER2 (human epidermal growth factor receptor 2), which is present in breast, ovary, and other cancers, and in detargeting from the natural receptors. Because the HER2-retargeted HSVs strictly depend on this receptor for infection, the viruses employed in preclinical studies were cultivated in HER2-positive cancer cells. The production of clinical-grade viruses destined for humans should avoid the use of cancer cells. Here, we engineered the R-213 recombinant, by insertion of a 20-amino-acid (aa) short peptide (named GCN4) in the gH of R-LM113; this recombinant was retargeted to HER2 through insertion in gD of a single-chain antibody (scFv) to HER2. Next, we generated a Vero cell line expressing an artificial receptor (GCN4R) whose N terminus consists of an scFv to GCN4 and therefore is capable of interacting with GCN4 present in gH of R-213. R-213 replicated as well as R-LM113 in SK-OV-3 cells, implying that addition of the GCN4 peptide was not detrimental to gH. R-213 grew to relatively high titers in Vero-GCN4R cells, efficiently spread from cell to cell, and killed both Vero-GCN4R and SK-OV-3 cells, as expected for an oncolytic virus. Altogether, Vero-GCN4R cells represent an efficient system for cultivation of retargeted oncolytic HSVs in non-cancer cells.IMPORTANCE There is growing interest in viruses as oncolytic agents, which can be administered in combination with immunotherapeutic compounds, including immune checkpoint inhibitors. The oncolytic HSV approved for clinical practice and those in clinical trials are attenuated viruses. An alternative to attenuation is a cancer specificity achieved by tropism retargeting to selected cancer receptors. However, the retargeted oncolytic HSVs strictly depend on cancer receptors for infection. Here, we devised a strategy for in vitro cultivation of retargeted HSVs in non-cancer cells. The strategy envisions a double-retargeting approach: one retargeting is via gD to the cancer receptor, and the second retargeting is via gH to an artificial receptor expressed in Vero cells. The double-retargeted HSV uses alternatively the two receptors to infect cancer cells or producer cells. A universal non-cancer cell line for growth of clinical-grade retargeted HSVs represents a step forward in the translational phase.
journal_name
J Viroljournal_title
Journal of virologyauthors
Leoni V,Gatta V,Casiraghi C,Nicosia A,Petrovic B,Campadelli-Fiume Gdoi
10.1128/JVI.00067-17subject
Has Abstractpub_date
2017-04-28 00:00:00issue
10eissn
0022-538Xissn
1098-5514pii
JVI.00067-17journal_volume
91pub_type
杂志文章abstract::Several viral determinants were shown to play a role in the ability of human immunodeficiency virus type 1 (HIV-1) to infect nondividing cells. In particular, Vpr and Gag matrix (MA) were recognized to be involved in the nuclear transport of the viral preintegration complex. The goal of the present study was to evalua...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.5.4104-4115.1998
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abstract::Encephalomyocarditis (EMC) virus (K-2 strain) was separated into two distinct peaks of optical density by chromatography on calcium phosphate, eluting at 0.17 and 0.31 m, respectively. The virus in these peaks could not be distinguished by infectivity (plaque-forming units), hemagglutinin activity, electron microscopi...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.1.2.308-316.1967
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journal_title:Journal of virology
pub_type: 杂志文章
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doi:10.1128/JVI.00584-06
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journal_title:Journal of virology
pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1128/JVI.65.12.7056-7060.1991
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.02723-05
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journal_title:Journal of virology
pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.12.10189-10196.1998
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journal_title:Journal of virology
pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.41.2.674-685.1982
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.6.5.685-689.1970
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.60.3.1075-1084.1986
更新日期:1986-12-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.12.6.1522-1533.1973
更新日期:1973-12-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.5.4024-4031.1997
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:1993-02-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00489-08
更新日期:2008-10-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00088-08
更新日期:2008-08-01 00:00:00
abstract::Efforts to develop a vaccine against human immunodeficiency virus type 1 (HIV-1) are complicated by resistance of virus to neutralization. The neutralization resistance phenotype of HIV-1 has been linked to high infectivity. We studied the mechanisms determining this phenotype using clones of the T-cell-line-adapted (...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.77.1.560-570.2003
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