Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis

Nichols, Daniel Brian; Martini, William De; Cottrell, Jessica

doi:10.3390/v9080215

Cited by 58 publications

(34 citation statements)

References 294 publications

(497 reference statements)

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“…Our results are consistent with the enhanced tumor selectivity of a VACV Western Reserve strain harboring a double deletion of two anti-apoptosis genes (SPI-1 and SPI-2) 31 . Other VACV strains encode other virulence factors with anti-apoptotic activity 32 . Future investigations should examine the potential of deleting additional anti-apoptotic factors to improve poxvirus vectors as OVs.…”

Section: Discussionsupporting

confidence: 83%

Deletion of Apoptosis Inhibitor F1L in Vaccinia Virus Increases Safety and Oncolysis for Cancer Therapy

Pelin

Foloppe

Petryk

et al. 2019

Molecular Therapy - Oncolytics

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Vaccinia virus (VACV) possesses a great safety record as a smallpox vaccine and has been intensively used as an oncolytic virus against various types of cancer over the past decade. Different strategies were developed to make VACV safe and selective to cancer cells. Leading clinical candidates, such as Pexa-Vec, are attenuated through deletion of the viral thymidine kinase (TK) gene, which limits virus growth to replicate in cancer tissue. However, tumors are not the only tissues whose metabolic activity can overcome the lack of viral TK. In this study, we sought to further increase the tumor-specific replication and oncolytic potential of Copenhagen strain VACV ΔTK. We show that deletion of the anti-apoptosis viral gene F1L not only increases the safety of the Copenhagen ΔTK virus but also improves its oncolytic activity in an aggressive glioblastoma model. The additional loss of F1L does not affect VACV replication capacity, yet its ability to induce cancer cell death is significantly increased. Our results also indicate that cell death induced by the Copenhagen ΔTK/F1L mutant releases more immunogenic signals, as indicated by increased levels of IL-1β production. A cytotoxicity screen in an NCI-60 panel shows that the ΔTK/F1L virus induces faster tumor cell death in different cancer types. Most importantly, we show that, compared to the TK-deleted virus, the ΔTK/F1L virus is attenuated in human normal cells and causes fewer pox lesions in murine models. Collectively, our findings describe a new oncolytic vaccinia deletion strain that improves safety and increases tumor cell killing.

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Section: Discussionsupporting

confidence: 83%

Deletion of Apoptosis Inhibitor F1L in Vaccinia Virus Increases Safety and Oncolysis for Cancer Therapy

Pelin

Foloppe

Petryk

et al. 2019

Molecular Therapy - Oncolytics

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“…Another class of interesting targets are the viral genes involved in cell death [42, 43]. Previously, we showed that deletion of the Spi-2/Spi-1 genes from VV renders it highly-attenuated in normal tissue, yet it retains replication competence in cancer cells and functions as a potent oncolytic VV [44].…”

Section: Biology Of Vaccinia Virusmentioning

confidence: 99%

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

Guo

et al. 2019

j. immunotherapy cancer

211

170

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Cancer vaccines and oncolytic immunotherapy are promising treatment strategies with potential to provide greater clinical benefit to patients with advanced-stage cancer. In particular, recombinant vaccinia viruses (VV) hold great promise as interventional agents. In this article, we first summarize the current understanding of virus biology and viral genes involved in host-virus interactions to further improve the utility of these agents in therapeutic applications. We then discuss recent findings from basic and clinical studies using VV as cancer vaccines and oncolytic immunotherapies. Despite encouraging results gleaned from translational studies in animal models, clinical trials implementing VV vectors alone as cancer vaccines have yielded largely disappointing results. However, the combination of VV vaccines with alternate forms of standard therapies has resulted in superior clinical efficacy. For instance, combination regimens using TG4010 (MVA-MUC1-IL2) with first-line chemotherapy in advanced-stage non-small cell lung cancer or combining PANVAC with docetaxel in the setting of metastatic breast cancer have clearly provided enhanced clinical benefits to patients. Another novel cancer vaccine approach is to stimulate anti-tumor immunity via STING activation in Batf3-dependent dendritic cells (DC) through the use of replication-attenuated VV vectors. Oncolytic VVs have now been engineered for improved safety and superior therapeutic efficacy by arming them with immune-stimulatory genes or pro-apoptotic molecules to facilitate tumor immunogenic cell death, leading to enhanced DC-mediated cross-priming of T cells recognizing tumor antigens, including neoantigens. Encouraging translational and early phase clinical results with Pexa-Vec have matured into an ongoing global phase III trial for patients with hepatocellular carcinoma. Combinatorial approaches, most notably those using immune checkpoint blockade, have produced exciting pre-clinical results and warrant the development of innovative clinical studies. Finally, we discuss major hurdles that remain in the field and offer some perspectives regarding the development of next generation VV vectors for use as cancer therapeutics.

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“…DNA viruses typically encode prosurvival factors in their genome. For example, poxvi- ruses express serpins, which inhibit the activity of cellular caspases (41). Cytomegaloviruses utilize virally encoded inhibitors of Bax and Bak, which trigger the intrinsic apoptotic pathway, for preventing cell death (42).…”

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confidence: 99%

Chandipura Virus Utilizes the Prosurvival Function of RelA NF-κB for Its Propagation

Bais

Ratra

Khan

et al. 2019

J Virol

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Chandipura virus (CHPV), a cytoplasmic RNA virus, has been implicated in several outbreaks of acute encephalitis in India. Despite the relevance of CHPV to human health, how the virus interacts with the host signaling machinery remains obscure. In response to viral infections, mammalian cells activate RelA/NF-B heterodimers, which induce genes encoding interferon beta (IFN-␤) and other immune mediators. Therefore, RelA is generally considered to be an antiviral transcription factor. However, RelA activates a wide spectrum of genes in physiological settings, and there is a paucity of direct genetic evidence substantiating antiviral RelA functions. Using mouse embryonic fibroblasts, we genetically dissected the role of RelA in CHPV pathogenesis. We found that CHPV indeed activated RelA and that RelA deficiency abrogated the expression of IFN-␤ in response to virus infections. Unexpectedly, infection of Rela Ϫ/Ϫ fibroblasts led to a decreased CHPV yield. Our investigation clarified that RelA-dependent synthesis of prosurvival factors restrained infection-inflicted cell death and that exacerbated cell death processes prevented multiplication of CHPV in RelAdeficient cells. Chikungunya virus, a cytopathic RNA virus associated also with epidemics, required RelA, and Japanese encephalitis virus, which produced relatively minor cytopathic effects in fibroblasts, circumvented the need of RelA for their propagation. In sum, we documented a proviral function of the pleiotropic factor RelA linked to its prosurvival properties. RelA promoted the growth of cytopathic RNA viruses by extending the life span of infected cells, which serve as the replicative niche of intracellular pathogens. We argue that our finding bears significance for understanding host-virus interactions and may have implications for antiviral therapeutic regimes. IMPORTANCE RelA/NF-B participates in a wide spectrum of physiological processes, including shaping immune responses against invading pathogens. In virusinfected cells, RelA typically induces the expression of IFN-␤, which restrains viral propagation in neighboring cells involving paracrine mechanisms. Our study suggested that RelA might also play a proviral role. A cell-autonomous RelA activity amplified the yield of Chandipura virus, a cytopathic RNA virus associated with human epidemics, by extending the life span of infected cells. Our finding necessitates a substantial revision of our understanding of host-virus interactions and indicates a dual role of NF-B signaling during the course of RNA virus infections. Our study also bears significance for therapeutic regimes which alter NF-B activities while alleviating the viral load.

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Poxviruses Utilize Multiple Strategies to Inhibit Apoptosis

Cited by 58 publications

References 294 publications

Deletion of Apoptosis Inhibitor F1L in Vaccinia Virus Increases Safety and Oncolysis for Cancer Therapy

Deletion of Apoptosis Inhibitor F1L in Vaccinia Virus Increases Safety and Oncolysis for Cancer Therapy

Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics

Chandipura Virus Utilizes the Prosurvival Function of RelA NF-κB for Its Propagation

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