Abstract:
:Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells, and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent against several cancers. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and if reovirus-induced cytotoxicity of breast cancer cells can be enhanced by modulating the activity of host molecules and pathways. Here, we generated reassortant reoviruses by forward genetics with enhanced infective and cytotoxic properties in triple-negative breast cancer cells. From a high-throughput screen of small-molecule inhibitors, we identified topoisomerase inhibitors as a class of drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of triple-negative breast cancer cells with topoisomerase inhibitors activates DNA damage response pathways, and reovirus infection induces robust production of type III, but not type I, interferon (IFN). Although type I and type III IFNs can activate STAT1 and STAT2, triple-negative breast cancer cellular proliferation is only negatively affected by type I IFN. Together, these data show that reassortant viruses with a novel genetic composition generated by forward genetics in combination with topoisomerase inhibitors more efficiently infect and kill triple-negative breast cancer cells.IMPORTANCE Patients afflicted by triple-negative breast cancer have decreased survival and limited therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, we generated two novel reoviruses that more efficiently infect and kill triple-negative breast cancer cells. We show that infection in the presence of DNA-damaging agents enhances infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a combination of a genetically engineered oncolytic reovirus and topoisomerase inhibitors may provide a potent therapeutic option for patients afflicted with triple-negative breast cancer.
journal_name
J Viroljournal_title
Journal of virologyauthors
Rodríguez Stewart RM,Berry JTL,Berger AK,Yoon SB,Hirsch AL,Guberman JA,Patel NB,Tharp GK,Bosinger SE,Mainou BAdoi
10.1128/JVI.01411-19subject
Has Abstractpub_date
2019-11-13 00:00:00issue
23eissn
0022-538Xissn
1098-5514pii
JVI.01411-19journal_volume
93pub_type
杂志文章abstract::Here we present the first complete genomic sequence of Marek's disease virus serotype 3 (MDV3), also known as turkey herpesvirus (HVT). The 159,160-bp genome encodes an estimated 99 putative proteins and resembles alphaherpesviruses in genomic organization and gene content. HVT is very similar to MDV1 and MDV2 within ...
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pub_type: 杂志文章
doi:10.1128/JVI.75.2.971-978.2001
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abstract::We have developed a high-throughput sequencing (HTS) workflow for investigating paramyxovirus transcription and replication. We show that sequencing of oligo(dT)-selected polyadenylated mRNAs, without considering the orientation of the RNAs from which they had been generated, cannot accurately be used to analyze the a...
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journal_title:Journal of virology
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doi:10.1128/JVI.01152-06
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abstract::Murine gammaherpesvirus 68 (gammaHV68; also known as MHV-68) can establish a latent infection in both inbred and outbred strains of mice and, as such, provides a tractable small-animal model to address mechanisms and cell types involved in the establishment and maintenance of chronic gammaherpesvirus infection. Latenc...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.77.15.8310-8321.2003
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abstract::A porcine rotavirus (prv), variant 4F, isolated in tissue culture from the feces of a Chinese pig with diarrhea, was found to have become highly pathogenic when passaged in gnotobiotic piglets (J. C. Bridger, B. Burke, G. M. Beards, and U. Desselberger, J. Gen. Virol. 73:3011-3015, 1992). Comparison with the closely r...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.1.853-857.1997
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abstract::The entire measles virus (MV) hemagglutinin (HA)-coding region was reconstructed from cloned cDNAs and used as part of a hybrid transcription unit to replace a region of the adenovirus type 5 genome corresponding to the entire E1a transcription unit and most of the E1b transcription unit. The resulting recombinant vir...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.62.8.2718-2727.1988
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abstract::The ubiquitous human polyomavirus JC (JCV) is a small double-stranded DNA virus that establishes a persistent infection, and it is often transmitted from parents to children. There are at least 14 subtypes of the virus associated with different human populations. Because of its presumed codivergence with humans, JCV h...
journal_title:Journal of virology
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abstract::A specific endoribonucleolytic activity was detected when detergent-lysed vesicular stomatitis of Sendai virus was incubated with the precursor to Escherichia coli tRNA Tyr. The cleavage products produced and the characteristics of the reaction were similar to those previously reported for human KB cell RNase NU. Like...
journal_title:Journal of virology
pub_type: 杂志文章
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abstract::Varicella-zoster virus (VZV) encodes within its unique long region a gene product with protein kinase motifs. In a previous study, we demonstrated that immunoprecipitated VZV open reading frame (ORF) 47 protein was associated with a functional protein kinase activity, on the basis of its ability to both autophosphoryl...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.3.1350-1359.1994
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abstract::Influenza viruses unable to express NS1 protein (delNS1) replicate poorly and induce large amounts of interferon (IFN). They are therefore considered candidate viruses for live-attenuated influenza vaccines. Their attenuated replication is generally assumed to result from the inability to counter the antiviral host re...
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.30.2.453-461.1979
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abstract::The Epstein-Barr virus BZLF1 gene product ZEBRA is a DNA-binding protein that is partially homologous to c-Fos, binds specifically to AP-1 sites, and can induce the lytic cycle in latently infected B lymphocytes. Induction of the viral lytic cycle can also be achieved by treatment with the phorbol ester 12-O-tetrade-c...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.64.9.4549-4552.1990
更新日期:1990-09-01 00:00:00
abstract::We have demonstrated that a liposomal array of well-ordered trimers enhances B cell activation, germinal center formation, and the elicitation of tier-2 autologous neutralizing antibodies. Previously, we coupled well-ordered cleavage-independent NFL trimers via their C-terminal polyhistidine tails to nickel lipids int...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00443-17
更新日期:2017-07-27 00:00:00
abstract::Turkeys inoculated with spleen extracts from lymphoproliferative disease (LPD)-affected birds developed viremia, followed by typical LPD lesions. Electron microscopy and biochemical characterization established that the virus present in the blood of infected turkeys is a type C retrovirus. The viral particles possess ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.30.1.351-357.1979
更新日期:1979-04-01 00:00:00
abstract::Mother-to-child transmission can occur in utero, mainly intrapartum and postpartum in case of breastfeeding. In utero transmission is highly restricted and results in selection of viral variant from the mother to the child. We have developed an in vitro system that mimics the interaction between viruses, infected cell...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.10.4780-4791.2001
更新日期:2001-05-01 00:00:00
abstract::Kaposi's sarcoma-associated herpesvirus (KSHV) (also called human herpesvirus 8) is consistently found in Kaposi's sarcoma lesions and in body-cavity-based lymphomas. A 17-kb KSHV lambda clone was obtained directly from a Kaposi's sarcoma lesion. DNA sequence analysis of this clone identified an open reading frame whi...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.3.1984-1991.1997
更新日期:1997-03-01 00:00:00
abstract::Early sensing of viral components or infection-induced tissue damage is a prerequisite for the successful control of pathogenic viruses by the host innate immune system. Recent results from our laboratory show how immune cells use the DNA-sensing machinery to detect intracellular damage generated early during infectio...
journal_title:Journal of virology
pub_type: 杂志文章,评审
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更新日期:2017-06-26 00:00:00
abstract::Innate immunity provides an immediate defense against infection after host cells sense danger signals from microbes. Endoplasmic reticulum (ER) stress arises from accumulation of misfolded/unfolded proteins when protein load overwhelms the ER folding capacity, which activates the unfolded protein response (UPR) to res...
journal_title:Journal of virology
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.11.5288-5301.2001
更新日期:2001-06-01 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 (...
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.10.4448-4455.2000
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.18.3.1131-1133.1976
更新日期:1976-06-01 00:00:00
abstract::High-risk human papillomaviruses encode two oncogenes, E6 and E7, expressed in nearly all cervical cancers. Although E7 protein is best known for its ability to inactivate the retinoblastoma tumor suppressor protein, pRb, many other activities for E7 have been proposed in in vitro studies. Herein, we describe studies ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.17.11392-11402.2005
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journal_title:Journal of virology
pub_type: 杂志文章
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abstract::Influenza virus particles bind rapidly to vesicular stomatitis, Sindbis, or Rauscher murine leukemia virus particles, forming mixed aggregates demonstrable by electron microscopy. The normal hemagglutinating property of influenza virus is inhibited by these viruses, providing a rapid quantitative assay. Prior treatmen...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.14.5.1307-1309.1974
更新日期:1974-11-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.65.12.6705-6713.1991
更新日期:1991-12-01 00:00:00
abstract::ICP0, an alpha (immediate-early) protein of herpes simplex virus 1, performs at least two key functions. It blocks inhibition of viral-gene expression by interferon, a function dependent on the degradation of the ND10 components PML and SP100 by the ubiquitin ligase expressed by the RING finger (RF), and it blocks sil...
journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2009-01-01 00:00:00
abstract::We investigated the susceptibilities of Syrian golden hamsters to transmissible spongiform encephalopathy agents from cattle. We report efficient transmission of the L-type atypical bovine spongiform encephalopathy (BSE) agent into hamsters. Importantly, hamsters were also susceptible to the transmissible mink encepha...
journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2011-02-01 00:00:00
abstract::The purpose of this study was to define the relationship between herpes simplex virus (HSV) latency and in vivo ganglionic reactivation. Groups of mice with numbers of latently infected neurons ranging from 1.9 to 24% were generated by varying the input titer of wild-type HSV type 1 strain 17syn+. Reactivation of the ...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.8.6888-6892.1998
更新日期:1998-08-01 00:00:00
abstract::Lethal, amber mutations in T4 genes 46 and 47 cause incomplete degradation of host DNA, premature arrest of phage DNA synthesis, accumulation of abnormal DNA replication intermediates, and defective recombination. These phenotypes can be explained by the hypothesis that genes 46 and 47 control a DNA exonuclease, but i...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.40.1.65-77.1981
更新日期:1981-10-01 00:00:00