STAT3 Activation Promotes Oncolytic HSV1 Replication in Glioma Cells

Okemoto, Kazuo; Wagner, Benjamin; Meisen, Hans; Haseley, Amy; Kaur, Balveen; Chiocca, E. Antonio

doi:10.1371/journal.pone.0071932

Cited by 27 publications

(29 citation statements)

References 19 publications

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“…Cytokines and chemokines derived from oHSV-infected tumor cells or cells of the tumor microenvironment limit oHSV replication and spread within the tumor and further induce stronger innate immune responses [20,21]. Chemokines CXCL9 (MIG) and CXCL10 (IP-10) are important in limiting HSV infections, recruiting natural killer (NK) and CD8 + T cells to the CNS [21].…”

Section: Host Responses Against Hsv Infectionmentioning

confidence: 99%

Oncolytic herpes simplex virus interactions with the host immune system

Saha

Wakimoto

Rabkin

2016

Current Opinion in Virology

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Oncolytic viruses (OVs), like oncolytic herpes simplex virus (oHSV), are genetically engineered to selectively replicate in and kill cancer cells, while sparing normal cells. Initial OV infection, cell death, and subsequent OV propagation within the tumor microenvironment leads to a cascade of host responses (innate and adaptive), reflective of natural anti-viral immune responses. These host-virus interactions are critical to the balance between OV activities, anti-viral immune responses limiting OV, and induction of anti-tumor immunity. The host response against oHSV is complex, multifaceted, and modulated by the tumor microenvironment and immunosuppression. As a successful pathogen, HSV has multiple mechanisms to evade such host responses. In this review, we will discuss these mechanisms and HSV evasion, and how they impact oHSV therapy.

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Section: Host Responses Against Hsv Infectionmentioning

confidence: 99%

Oncolytic herpes simplex virus interactions with the host immune system

Saha

Wakimoto

Rabkin

2016

Current Opinion in Virology

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“…Thus, new level of control of cellular functions by HSV-1 suggests that persistent NF-κB/p65/RelA activation in HSV-1-infected cells, rather than being a host response to the virus, may play a positive role in promoting efficient viral replication [18]. As for STAT3, its signaling was shown to promote oncolytic HSV-1 replication, likely by inhibiting the IFN-γ response [19]. As virus-host interactions are crucial for the outcome of infections, our computational findings of multiple potentially active DREs in promoter region of HSV-1 genes, as well as in genes encoding major host cell cytokines, all strongly suggest that body burden subnanomolar dioxin is able to promote HSV-1 infection.…”

Section: Resultsmentioning

confidence: 99%

Transactivation by Body Burden Dioxin of Herpes Simplex Virus Genes and Cytokines Genes can Weaken the Host Antiviral Defense

Ib¹,

Js²,

Dy³

2017

MOJCSR

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Among several common human viruses, the neurotropic HSV-1 was suggested a target of host cell dioxin receptor transcriptional (AhR-Arnt) complex. The latter was proven to up-regulate the expression of mammalian and viral genes containing multiple dioxin-responsive elements (DRE). Here, 7 to 8 potentially active DRE in the regulatory regions of five HSV-1 genes, including critical immediate-early (IE) ones, were revealed by SITECON, a tool for transcription factor binding sites recognition. With regard to the possession of abundant promoter DRE, HSV-1 resembles another herpes virus, CMV, and as well as with CMV, it was experimentally demonstrated that the HSV-1 might be trans-activated in host cells by concentrations of 2,3,7,8-TCDD corresponding to current body burden of dioxin in general population. The above approach was applied also to chemokines and cytokines the recruitment of those involves in the first line of defense against HSV-1 infections together with production of IFN-α/β. Thus in cilico studies revealed that genes encoding "antiviral" IFN-γ, IL-1β, IL-6, IL-18, NF-kB1 (p50), TNF-α each contain just one or two promoter DRE, whereas genes encoding "pro-viral" RANTES/CCL5, NF-kB3/p65/RelA and STAT3 possess seven to nine active 5'-upstream DRE. As virus-host interactions are crucial for the outcome of infections, our findings of multiple potentially active DRE in promoter region of HSV-1 genes, as well as in genes encoding major host cell "pro-viral" cytokines, this suggests that a subnanomolar dioxin in host cell is able to promote HSV-1 infection. From a clinical standpoint, an inhibition of dioxin can cause augmentation of HSV-1 infections which can be achieved with inhibitors of dioxin binding to host cell Ah receptor, or blockage of activated AhR-Arnt transcriptional complex binding to the viral promoter DRE.

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“…A previous study showed that genetic or pharmacologic activation of STAT3 in glioma cells enhanced oHSV replication and cytotoxicity [18]. And McCartney et al also proved that HCV replication increase STAT3 activation; in turn activation of STAT3 increases HCV replication by modulating microtubule dynamics Fig.…”

Section: Discussionmentioning

confidence: 97%