Research

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24 pages, 5858 KiB

Open AccessArticle

Oclacitinib and Myxoma Virus Therapy in Dogs with High-Grade Soft Tissue Sarcoma

by Laura V. Ashton, Kristen M. Weishaar, Bernard Séguin and Amy L. MacNeill

Biomedicines 2023, 11(9), 2346; https://doi.org/10.3390/biomedicines11092346 - 23 Aug 2023

Viewed by 1364

Human rhabdomyosarcomas are rarely cured by surgical resection alone. This is also true for high-grade soft tissue sarcomas in dogs. Dogs with spontaneous sarcoma are good models for clinical responses to new cancer therapies. Strategic combinations of immunotherapy and oncolytic virotherapy (OV) could [...] Read more.

Human rhabdomyosarcomas are rarely cured by surgical resection alone. This is also true for high-grade soft tissue sarcomas in dogs. Dogs with spontaneous sarcoma are good models for clinical responses to new cancer therapies. Strategic combinations of immunotherapy and oncolytic virotherapy (OV) could improve treatment responses in canine and human cancer patients. To develop an appropriate combination of immunotherapy and OV for dogs with soft tissue sarcoma (STS), canine cancer cells were inoculated with myxoma viruses (MYXVs) and gene transcripts were quantified. Next, the cytokine concentrations in the canine cancer cells were altered to evaluate their effect on MYXV replication. These studies indicated that, as in murine and human cells, type I interferons (IFN) play an important role in limiting MYXV replication in canine cancer cells. To reduce type I IFN production during OV, oclacitinib (a JAK1 inhibitor) was administered twice daily to dogs for 14 days starting ~7 days prior to surgery. STS tumors were excised, and MYXV deleted for serp2 (MYXV∆SERP2) was administered at the surgical site at two time points post-operatively to treat any remaining microscopic tumor cells. Tumor regrowth in dogs treated with OV was decreased relative to historical controls. However, regrowth was not further inhibited in patients given combination therapy. Full article

(This article belongs to the Special Issue Poxviruses: From Pathophysiology to Novel Therapeutic Approaches)

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13 pages, 2058 KiB

Open AccessArticle

Myxomavirus Serp-1 Protein Ameliorates Inflammation in a Mouse Model of Duchenne Muscular Dystrophy

by Alexander B. Andre, Liqiang Zhang, Jalen D. Nix, Nora Elmadbouly, Alexandra R. Lucas, Jeanne Wilson-Rawls and Alan Rawls

Biomedicines 2022, 10(5), 1154; https://doi.org/10.3390/biomedicines10051154 - 17 May 2022

Cited by 3 | Viewed by 1949

Abstract

Duchenne muscular dystrophy is an X-linked disease afflicting 1 in 3500 males that is characterized by muscle weakness and wasting during early childhood, and loss of ambulation and death by early adulthood. Chronic inflammation due to myofiber instability leads to fibrosis, which is [...] Read more.

Duchenne muscular dystrophy is an X-linked disease afflicting 1 in 3500 males that is characterized by muscle weakness and wasting during early childhood, and loss of ambulation and death by early adulthood. Chronic inflammation due to myofiber instability leads to fibrosis, which is a primary cause of loss of ambulation and cardiorespiratory insufficiency. Current standard of care focuses on reducing inflammation with corticosteroids, which have serious adverse effects. It is imperative to identify alternate immunosuppressants as treatments to reduce fibrosis and mortality. Serp-1, a Myxoma virus-derived 55 kDa secreted glycoprotein, has proven efficacy in a range of animal models of acute inflammation, and its safety and efficacy has been shown in a clinical trial. In this initial study, we examined whether pegylated Serp-1 (PEGSerp-1) treatment would ameliorate chronic inflammation in a mouse model for Duchenne muscular dystrophy. Our data revealed a significant reduction in diaphragm fibrosis and increased myofiber diameter, and significantly decreased pro-inflammatory M1 macrophage infiltration. The M2a macrophage and overall T cell populations showed no change. These data demonstrate that treatment with this new class of poxvirus-derived immune-modulating serpin has potential as a therapeutic approach designed to ameliorate DMD pathology and facilitate muscle regeneration. Full article

(This article belongs to the Special Issue Poxviruses: From Pathophysiology to Novel Therapeutic Approaches)

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37 pages, 17686 KiB

Open AccessArticle

Poxviruses Bearing DNA Polymerase Mutations Show Complex Patterns of Cross-Resistance

by Graciela Andrei, Pierre Fiten, Marcela Krečmerová, Ghislain Opdenakker, Dimitrios Topalis and Robert Snoeck

Biomedicines 2022, 10(3), 580; https://doi.org/10.3390/biomedicines10030580 - 01 Mar 2022

Cited by 10 | Viewed by 2260

Abstract

Despite the eradication of smallpox four decades ago, poxviruses continue to be a threat to humans and animals. The arsenal of anti-poxvirus agents is very limited and understanding mechanisms of resistance to agents targeting viral DNA polymerases is fundamental for the development of [...] Read more.

Despite the eradication of smallpox four decades ago, poxviruses continue to be a threat to humans and animals. The arsenal of anti-poxvirus agents is very limited and understanding mechanisms of resistance to agents targeting viral DNA polymerases is fundamental for the development of antiviral therapies. We describe here the phenotypic and genotypic characterization of poxvirus DNA polymerase mutants isolated under selective pressure with different acyclic nucleoside phosphonates, including HPMPC (cidofovir), cHPMPC, HPMPA, cHPMPA, HPMPDAP, HPMPO-DAPy, and PMEO-DAPy, and the pyrophosphate analogue phosphonoacetic acid. Vaccinia virus (VACV) and cowpox virus drug-resistant viral clones emerging under drug pressure were characterized phenotypically (drug-susceptibility profile) and genotypically (DNA polymerase sequencing). Different amino acid changes in the polymerase domain and in the 3′-5′ exonuclease domain were linked to drug resistance. Changes in the 3′-5′ domain emerged earlier than in the polymerase domain when viruses acquired a combination of mutations. Our study highlights the importance of poxvirus DNA polymerase residues 314, 613, 684, 688, and 851, previously linked to drug resistance, and identified several novel mutations in the 3′-5′ exonuclease domain (M313I, F354L, D480Y) and in the DNA polymerase domain (A632T, T831I, E856K, L924F) associated with different drug-susceptibility profiles. Furthermore, a combination of mutations resulted in complex patterns of cross-resistance. Modeling of the VACV DNA polymerase bearing the newly described mutations was performed to understand the effects of these mutations on the structure of the viral enzyme. We demonstrated the emergence of drug-resistant DNA polymerase mutations in complex patterns to be considered in case such mutations should eventually arise in the clinic. Full article

(This article belongs to the Special Issue Poxviruses: From Pathophysiology to Novel Therapeutic Approaches)

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22 pages, 2117 KiB

Open AccessArticle

A Novel Orf Virus D1701-VrV-Based Dengue Virus (DENV) Vaccine Candidate Expressing HLA-Specific T Cell Epitopes: A Proof-of-Concept Study

by Alena Reguzova, Nico Fischer, Melanie Müller, Ferdinand Salomon, Thomas Jaenisch and Ralf Amann

Biomedicines 2021, 9(12), 1862; https://doi.org/10.3390/biomedicines9121862 - 08 Dec 2021

Cited by 2 | Viewed by 2736

Abstract

Although dengue virus (DENV) affects almost half of the world’s population there are neither preventive treatments nor any long-lasting and protective vaccines available at this time. The complexity of the protective immune response to DENV is still not fully understood. The most advanced [...] Read more.

Although dengue virus (DENV) affects almost half of the world’s population there are neither preventive treatments nor any long-lasting and protective vaccines available at this time. The complexity of the protective immune response to DENV is still not fully understood. The most advanced vaccine candidates focus specifically on humoral immune responses and the production of virus-neutralizing antibodies. However, results from several recent studies have revealed the protective role of T cells in the immune response to DENV. Hence, in this study, we generated a novel and potent DENV vaccine candidate based on an Orf virus (ORFV, genus Parapoxvirus) vector platform engineered to encode five highly conserved or cross-reactive DENV human leukocyte antigen (HLA)-A*02- or HLA-B*07-restricted epitopes as minigenes (ORFV-DENV). We showed that ORFV-DENV facilitates the in vitro priming of CD8⁺ T cells from healthy blood donors based on responses to each of the encoded immunogenic peptides. Moreover, we demonstrated that peripheral blood mononuclear cells isolated from clinically confirmed DENV-positive donors stimulated with ORFV-DENV generate cytotoxic T cell responses to at least three of the expressed DENV peptides. Finally, we showed that ORFV-DENV could activate CD8⁺ T cells isolated from donors who had recovered from Zika virus (ZIKV) infection. ZIKV belongs to the same virus family (Flaviviridae) and has epitope sequences that are homologous to those of DENV. We found that highly conserved HLA-B*07-restricted ZIKV and DENV epitopes induced functional CD8⁺ T cell responses in PBMCs isolated from confirmed ZIKV-positive donors. In summary, this proof-of-concept study characterizes a promising new ORFV D1701-VrV-based DENV vaccine candidate that induces broad and functional epitope-specific CD8⁺ T cell responses. Full article

(This article belongs to the Special Issue Poxviruses: From Pathophysiology to Novel Therapeutic Approaches)

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21 pages, 2553 KiB

Open AccessArticle

Modulation of Early Host Innate Immune Response by an Avipox Vaccine Virus’ Lateral Body Protein

by Efstathios S. Giotis, Stephen M. Laidlaw, Susanna R. Bidgood, David Albrecht, Jemima J. Burden, Rebecca C. Robey, Jason Mercer and Michael A. Skinner

Biomedicines 2020, 8(12), 634; https://doi.org/10.3390/biomedicines8120634 - 19 Dec 2020

Cited by 4 | Viewed by 3363

Abstract

The avian pathogen fowlpox virus (FWPV) has been successfully used as a vaccine vector in poultry and humans, but relatively little is known about its ability to modulate host antiviral immune responses in these hosts, which are replication-permissive and nonpermissive, respectively. FWPV is [...] Read more.

The avian pathogen fowlpox virus (FWPV) has been successfully used as a vaccine vector in poultry and humans, but relatively little is known about its ability to modulate host antiviral immune responses in these hosts, which are replication-permissive and nonpermissive, respectively. FWPV is highly resistant to avian type I interferon (IFN) and able to completely block the host IFN-response. Microarray screening of host IFN-regulated gene expression in cells infected with 59 different, nonessential FWPV gene knockout mutants revealed that FPV184 confers immunomodulatory capacity. We report that the FPV184-knockout virus (FWPVΔ184) induces the cellular IFN response as early as 2 h postinfection. The wild-type, uninduced phenotype can be rescued by transient expression of FPV184 in FWPVΔ184-infected cells. Ectopic expression of FPV184 inhibited polyI:C activation of the chicken IFN-β promoter and IFN-α activation of the chicken Mx1 promoter. Confocal and correlative super-resolution light and electron microscopy demonstrated that FPV184 has a functional nuclear localisation signal domain and is packaged in the lateral bodies of the virions. Taken together, these results provide a paradigm for a late poxvirus structural protein packaged in the lateral bodies, capable of suppressing IFN induction early during the next round of infection. Full article

(This article belongs to the Special Issue Poxviruses: From Pathophysiology to Novel Therapeutic Approaches)

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Review

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17 pages, 2431 KiB

Open AccessReview

Small Hero with Great Powers: Vaccinia Virus E3 Protein and Evasion of the Type I IFN Response

by Mateusz Szczerba, Sambhavi Subramanian, Kelly Trainor, Megan McCaughan, Karen V. Kibler and Bertram L. Jacobs

Biomedicines 2022, 10(2), 235; https://doi.org/10.3390/biomedicines10020235 - 22 Jan 2022

Cited by 15 | Viewed by 4657

Abstract

Poxviridae have developed a plethora of strategies to evade innate and adaptive immunity. In this review, we focused on the vaccinia virus E3 protein, encoded by the E3L gene. E3 is present within the Chordopoxvirinae subfamily (with the exception of the avipoxviruses and [...] Read more.

Poxviridae have developed a plethora of strategies to evade innate and adaptive immunity. In this review, we focused on the vaccinia virus E3 protein, encoded by the E3L gene. E3 is present within the Chordopoxvirinae subfamily (with the exception of the avipoxviruses and molluscum contagiosum virus) and displays pleiotropic effects on the innate immune system. Initial studies identified E3 as a double-stranded RNA (dsRNA)-binding protein (through its C terminus), able to inhibit the activation of protein kinase dependent on RNA (PKR) and the 2′5′-oligoadenylate synthetase (OAS)/RNase L pathway, rendering E3 a protein counteracting the type I interferon (IFN) system. In recent years, N-terminal mutants of E3 unable to bind to Z-form nucleic acids have been shown to induce the cellular death pathway necroptosis. This pathway was dependent on host IFN-inducible Z-DNA-binding protein 1 (ZBP1); full-length E3 is able to inhibit ZBP1-mediated necroptosis. Binding to what was identified as Z-RNA has emerged as a novel mechanism of counteracting the type I IFN system and has broadened our understanding of innate immunity against viral infections. This article gives an overview of the studies leading to our understanding of the vaccinia virus E3 protein function and its involvement in viral pathogenesis. Furthermore, a short summary of other viral systems is provided. Full article

(This article belongs to the Special Issue Poxviruses: From Pathophysiology to Novel Therapeutic Approaches)

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18 pages, 1245 KiB

Open AccessReview

Vaccinia Virus: From Crude Smallpox Vaccines to Elaborate Viral Vector Vaccine Design

by Onur Kaynarcalidan, Sara Moreno Mascaraque and Ingo Drexler

Biomedicines 2021, 9(12), 1780; https://doi.org/10.3390/biomedicines9121780 - 26 Nov 2021

Cited by 18 | Viewed by 5422

Abstract

Various vaccinia virus (VACV) strains were applied during the smallpox vaccination campaign to eradicate the variola virus worldwide. After the eradication of smallpox, VACV gained popularity as a viral vector thanks to increasing innovations in genetic engineering and vaccine technology. Some VACV strains [...] Read more.

Various vaccinia virus (VACV) strains were applied during the smallpox vaccination campaign to eradicate the variola virus worldwide. After the eradication of smallpox, VACV gained popularity as a viral vector thanks to increasing innovations in genetic engineering and vaccine technology. Some VACV strains have been extensively used to develop vaccine candidates against various diseases. Modified vaccinia virus Ankara (MVA) is a VACV vaccine strain that offers several advantages for the development of recombinant vaccine candidates. In addition to various host-restriction genes, MVA lacks several immunomodulatory genes of which some have proven to be quite efficient in skewing the immune response in an unfavorable way to control infection in the host. Studies to manipulate these genes aim to optimize the immunogenicity and safety of MVA-based viral vector vaccine candidates. Here we summarize the history and further work with VACV as a vaccine and present in detail the genetic manipulations within the MVA genome to improve its immunogenicity and safety as a viral vector vaccine. Full article

(This article belongs to the Special Issue Poxviruses: From Pathophysiology to Novel Therapeutic Approaches)

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13 pages, 831 KiB

Open AccessReview

Modified Vaccinia Virus Ankara as a Viral Vector for Vaccine Candidates against Chikungunya Virus

by Juan García-Arriaza, Mariano Esteban and Daniel López

Biomedicines 2021, 9(9), 1122; https://doi.org/10.3390/biomedicines9091122 - 31 Aug 2021

Cited by 5 | Viewed by 2710

Abstract

There is a need to develop a highly effective vaccine against the emerging chikungunya virus (CHIKV), a mosquito-borne Alphavirus that causes severe disease in humans consisting of acute febrile illness, followed by chronic debilitating polyarthralgia and polyarthritis. In this review, we provide a [...] Read more.

There is a need to develop a highly effective vaccine against the emerging chikungunya virus (CHIKV), a mosquito-borne Alphavirus that causes severe disease in humans consisting of acute febrile illness, followed by chronic debilitating polyarthralgia and polyarthritis. In this review, we provide a brief history of the development of the first poxvirus vaccines that led to smallpox eradication and its implications for further vaccine development. As an example, we summarize the development of vaccine candidates based on the modified vaccinia virus Ankara (MVA) vector expressing different CHIKV structural proteins, paying special attention to MVA-CHIKV expressing all of the CHIKV structural proteins: C, E3, E2, 6K and E1. We review the characterization of innate and adaptive immune responses induced in mice and nonhuman primates by the MVA-CHIKV vaccine candidate and examine its efficacy in animal models, with promising preclinical findings needed prior to the approval of human clinical trials. Full article

(This article belongs to the Special Issue Poxviruses: From Pathophysiology to Novel Therapeutic Approaches)

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30 pages, 3973 KiB

Open AccessReview

Battle Royale: Innate Recognition of Poxviruses and Viral Immune Evasion

by Huibin Yu, Ryan C. Bruneau, Greg Brennan and Stefan Rothenburg

Biomedicines 2021, 9(7), 765; https://doi.org/10.3390/biomedicines9070765 - 01 Jul 2021

Cited by 51 | Viewed by 6320

Abstract

Host pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs), which are molecular signatures shared by different pathogens. Recognition of PAMPs by PRRs initiate innate immune responses via diverse signaling pathways. Over recent decades, advances in our knowledge of innate immune sensing have [...] Read more.

Host pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs), which are molecular signatures shared by different pathogens. Recognition of PAMPs by PRRs initiate innate immune responses via diverse signaling pathways. Over recent decades, advances in our knowledge of innate immune sensing have enhanced our understanding of the host immune response to poxviruses. Multiple PRR families have been implicated in poxvirus detection, mediating the initiation of signaling cascades, activation of transcription factors, and, ultimately, the expression of antiviral effectors. To counteract the host immune defense, poxviruses have evolved a variety of immunomodulators that have diverse strategies to disrupt or circumvent host antiviral responses triggered by PRRs. These interactions influence the outcomes of poxvirus infections. This review focuses on our current knowledge of the roles of PRRs in the recognition of poxviruses, their elicited antiviral effector functions, and how poxviral immunomodulators antagonize PRR-mediated host immune responses. Full article

(This article belongs to the Special Issue Poxviruses: From Pathophysiology to Novel Therapeutic Approaches)

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