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The highly attenuated oncolytic recombinant vaccinia virus GLV-1h68: comparative genomic features and the contribution of F14.5L inactivation.

Zhang Q, Liang C, Yu YA, Chen N, Dandekar T, Szalay AA - Mol. Genet. Genomics (2009)

Bottom Line: The reduced pathogenicity of GLV-1h68 is confirmed in male mice bearing C6 rat glioma and in immunocompetent mice bearing B16-F10 murine melanoma.The contribution of foreign gene expression cassettes in the F14.5L, J2R and A56R loci is analyzed, in particular the contribution of F14.5L inactivation to the reduced virulence is demonstrated by comparing the virulence of GLV-1h68 with its F14.5L- and revertant viruses.GLV-1h68 is a promising engineered VACV variant for anticancer therapy with tumor-specific replication, reduced pathogenicity and benign tissue tropism.

View Article: PubMed Central - PubMed

Affiliation: Genelux Corporation, San Diego Science Center, 3030 Bunker Hill St., Ste. 310, San Diego, CA 92109, USA.

ABSTRACT
As a new anticancer treatment option, vaccinia virus (VACV) has shown remarkable antitumor activities (oncolysis) in preclinical studies, but potential infection of other organs remains a safety concern. We present here genome comparisons between the de novo sequence of GLV-1h68, a recombinant VACV, and other VACVs. The identified differences in open reading frames (ORFs) include genes encoding host-range selection, virulence and immune modulation proteins, e.g., ankyrin-like proteins, serine proteinase inhibitor SPI-2/CrmA, tumor necrosis factor (TNF) receptor homolog CrmC, semaphorin-like and interleukin-1 receptor homolog proteins. Phylogenetic analyses indicate that GLV-1h68 is closest to Lister strains but has lost several ORFs present in its parental LIVP strain, including genes encoding CrmE and a viral Golgi anti-apoptotic protein, v-GAAP. The reduced pathogenicity of GLV-1h68 is confirmed in male mice bearing C6 rat glioma and in immunocompetent mice bearing B16-F10 murine melanoma. The contribution of foreign gene expression cassettes in the F14.5L, J2R and A56R loci is analyzed, in particular the contribution of F14.5L inactivation to the reduced virulence is demonstrated by comparing the virulence of GLV-1h68 with its F14.5L- and revertant viruses. GLV-1h68 is a promising engineered VACV variant for anticancer therapy with tumor-specific replication, reduced pathogenicity and benign tissue tropism.

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GLV-1h68 genome map. Predicted ORFs and their lengths are represented by colored arrows. Sixty-one ORFs involved in host interactions and immune modulation are shown in blue. Located mostly in the central conserved region are genes involved in: viral structure and assembly (49 ORFs, shown in pink), metabolism (41 ORFs, shown in orange) and DNA replication, RNA transcription and modifications (28 ORFs, in green). The functions of 58 ORFs remain uncertain (marked with clear arrows). The three foreign insertions are marked in dark grey. The genome size is indicated on the right (nucleotides)
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Fig2: GLV-1h68 genome map. Predicted ORFs and their lengths are represented by colored arrows. Sixty-one ORFs involved in host interactions and immune modulation are shown in blue. Located mostly in the central conserved region are genes involved in: viral structure and assembly (49 ORFs, shown in pink), metabolism (41 ORFs, shown in orange) and DNA replication, RNA transcription and modifications (28 ORFs, in green). The functions of 58 ORFs remain uncertain (marked with clear arrows). The three foreign insertions are marked in dark grey. The genome size is indicated on the right (nucleotides)

Mentions: Based on the annotation, we classified the major ORFs into six functional categories. Figure 2 shows their distribution in the viral genome. Sixty-one ORFs were likely to be involved in host interactions and immune modulation, and most of these were found to be positioned in the left and right terminal regions and the edges of the central conserved region. Forty-nine ORFs encoding proteins involved in viral structure and assembly were located in the central conserved region, including viral core proteins, plaque forming, and EEV and IEV membrane proteins (pink). Genes involved in metabolism (41 ORFs, orange) and genes involved in DNA replication, RNA transcription and modifications (28 ORFs, green) were also located in the central conserved region. The functions of 58 ORFs remained uncertain or unidentified (marked with clear arrows). GL068 (F14.5L) was split into two parts by the RUC-GFP expression cassette (marked in gray, Fig. 2). Other foreign insertions included lacZ in the TK locus, and gusA in the HA locus.Fig. 2


The highly attenuated oncolytic recombinant vaccinia virus GLV-1h68: comparative genomic features and the contribution of F14.5L inactivation.

Zhang Q, Liang C, Yu YA, Chen N, Dandekar T, Szalay AA - Mol. Genet. Genomics (2009)

GLV-1h68 genome map. Predicted ORFs and their lengths are represented by colored arrows. Sixty-one ORFs involved in host interactions and immune modulation are shown in blue. Located mostly in the central conserved region are genes involved in: viral structure and assembly (49 ORFs, shown in pink), metabolism (41 ORFs, shown in orange) and DNA replication, RNA transcription and modifications (28 ORFs, in green). The functions of 58 ORFs remain uncertain (marked with clear arrows). The three foreign insertions are marked in dark grey. The genome size is indicated on the right (nucleotides)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2746888&req=5

Fig2: GLV-1h68 genome map. Predicted ORFs and their lengths are represented by colored arrows. Sixty-one ORFs involved in host interactions and immune modulation are shown in blue. Located mostly in the central conserved region are genes involved in: viral structure and assembly (49 ORFs, shown in pink), metabolism (41 ORFs, shown in orange) and DNA replication, RNA transcription and modifications (28 ORFs, in green). The functions of 58 ORFs remain uncertain (marked with clear arrows). The three foreign insertions are marked in dark grey. The genome size is indicated on the right (nucleotides)
Mentions: Based on the annotation, we classified the major ORFs into six functional categories. Figure 2 shows their distribution in the viral genome. Sixty-one ORFs were likely to be involved in host interactions and immune modulation, and most of these were found to be positioned in the left and right terminal regions and the edges of the central conserved region. Forty-nine ORFs encoding proteins involved in viral structure and assembly were located in the central conserved region, including viral core proteins, plaque forming, and EEV and IEV membrane proteins (pink). Genes involved in metabolism (41 ORFs, orange) and genes involved in DNA replication, RNA transcription and modifications (28 ORFs, green) were also located in the central conserved region. The functions of 58 ORFs remained uncertain or unidentified (marked with clear arrows). GL068 (F14.5L) was split into two parts by the RUC-GFP expression cassette (marked in gray, Fig. 2). Other foreign insertions included lacZ in the TK locus, and gusA in the HA locus.Fig. 2

Bottom Line: The reduced pathogenicity of GLV-1h68 is confirmed in male mice bearing C6 rat glioma and in immunocompetent mice bearing B16-F10 murine melanoma.The contribution of foreign gene expression cassettes in the F14.5L, J2R and A56R loci is analyzed, in particular the contribution of F14.5L inactivation to the reduced virulence is demonstrated by comparing the virulence of GLV-1h68 with its F14.5L- and revertant viruses.GLV-1h68 is a promising engineered VACV variant for anticancer therapy with tumor-specific replication, reduced pathogenicity and benign tissue tropism.

View Article: PubMed Central - PubMed

Affiliation: Genelux Corporation, San Diego Science Center, 3030 Bunker Hill St., Ste. 310, San Diego, CA 92109, USA.

ABSTRACT
As a new anticancer treatment option, vaccinia virus (VACV) has shown remarkable antitumor activities (oncolysis) in preclinical studies, but potential infection of other organs remains a safety concern. We present here genome comparisons between the de novo sequence of GLV-1h68, a recombinant VACV, and other VACVs. The identified differences in open reading frames (ORFs) include genes encoding host-range selection, virulence and immune modulation proteins, e.g., ankyrin-like proteins, serine proteinase inhibitor SPI-2/CrmA, tumor necrosis factor (TNF) receptor homolog CrmC, semaphorin-like and interleukin-1 receptor homolog proteins. Phylogenetic analyses indicate that GLV-1h68 is closest to Lister strains but has lost several ORFs present in its parental LIVP strain, including genes encoding CrmE and a viral Golgi anti-apoptotic protein, v-GAAP. The reduced pathogenicity of GLV-1h68 is confirmed in male mice bearing C6 rat glioma and in immunocompetent mice bearing B16-F10 murine melanoma. The contribution of foreign gene expression cassettes in the F14.5L, J2R and A56R loci is analyzed, in particular the contribution of F14.5L inactivation to the reduced virulence is demonstrated by comparing the virulence of GLV-1h68 with its F14.5L- and revertant viruses. GLV-1h68 is a promising engineered VACV variant for anticancer therapy with tumor-specific replication, reduced pathogenicity and benign tissue tropism.

Show MeSH
Related in: MedlinePlus