Correlates Between Host and Viral Transcriptional Program Associated with Different Oncolytic Vaccinia Virus Isolates

Abstract

Vaccinia virus (VACV) has emerged as an attractive tool in oncolytic virotherapy. VACV replication efficiency plays a crucial role in the therapeutic outcome. However, little is known about the influence of host factors on viral replication efficiency and permissiveness of a host cell line to infection and oncolysis. In this study, replication of the attenuated VACV GLV-1h68 strain and three wild-type VACV isolates was determined in two autologous human melanoma cell lines (888-MEL and 1936-MEL). Host gene expression and viral gene expression in infected cells were evaluated via respective expression array platforms.Microarray analyses followed by sequential statistical approaches characterized human genes that change specifically due to virus infection. Viral gene transcription correlated with viral replication in a time-dependent manner. A set of human genes revealed strong correlations with the respective viral gene expression. Finally we identified a set of human genes with possible predictive value for viral replication in an independent dataset.The results demonstrate a probable correlation between viral replication, early gene expression, and the respective host response, and thus a possible involvement of human host factors in viral early replication. The characterization of human target genes that influence viral replication could help answer the question of host cell permissiveness to oncolytic virotherapy and provide important information for the development of novel recombinant vaccinia viruses with improved features to enhance replication rate and hence trigger therapeutic outcome.

Molecular network, pathway, and functional analysis of time-dependent gene changes associated with pancreatic cancer susceptibility to oncolytic vaccinia virotherapy

“… 22 , 23 In a recent study by Morgan et al . 24 , EGFR inhibitors cetuximab and erlotinib was used in combination with gemcitabine for enhanced efficacy against pancreatic cancer. This pathway was significantly modulated by 24 hours after infection with GLV-1h153 in our study, with downregulation of the EGFR receptor, potentially mimicking effects of EGFR inhibitors.…”

Non-BRAF-targeted therapy, immunotherapy, and combination therapy for melanoma

“…Broadly, melanoma vaccines are classified into the following main categories: whole-cell vaccines (either autologous or allogeneic, prepared using melanoma cells or subcellular fraction); dendritic-cell (DC) vaccines (which take advantage of the highly specialization of DCs to present antigens and induce primary cellular immune responses); peptide vaccines (which use melanoma antigens to stimulate cytotoxic T lymphocytes response against tumor cells); ganglioside vaccines (which take advantage of the high expression of gangliosides on the surface of melanoma cells to generate an immune response against them); DNA vaccines (composed of naked DNA expression plasmids that include a gene encoding the target antigens from tumor cells); viral vector vaccines (in which a virus is used as vector of melanoma antigens); and oncolytic vaccine (in which an oncolytic virus replicating in cancer cells is used to mediate tumor cell lysis) [107][108][109][110].…”

Monitoring the Efficacy of Oncolytic Viruses via Gene Expression

“…Combination studies can potentially assess the correlation between the viral replication and the host response. Reinboth et al looked at two different human melanoma cell lines (888-MEL and 1936-MEL) ( 29 ). They infected the cell lines with an attenuated VACV GLV-1h68.…”