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Journal ArticleDOI

Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity

01 Nov 2013-Journal of General Virology (Microbiology Society)-Vol. 94, Iss: 11, pp 2367-2392
TL;DR: Three VACV immunomodulatory proteins function inside cells to inhibit apoptosis or signalling pathways that lead to the production of interferons and pro-inflammatory cytokines and chemokines and the potential to create more immunogenic VacV strains by manipulation of the gene encoding these proteins is discussed.
Abstract: Virus infection of mammalian cells is sensed by pattern recognition receptors and leads to an innate immune response that restricts virus replication and induces adaptive immunity. In response, viruses have evolved many countermeasures that enable them to replicate and be transmitted to new hosts, despite the host innate immune response. Poxviruses, such as vaccinia virus (VACV), have large DNA genomes and encode many proteins that are dedicated to host immune evasion. Some of these proteins are secreted from the infected cell, where they bind and neutralize complement factors, interferons, cytokines and chemokines. Other VACV proteins function inside cells to inhibit apoptosis or signalling pathways that lead to the production of interferons and pro-inflammatory cytokines and chemokines. In this review, these VACV immunomodulatory proteins are described and the potential to create more immunogenic VACV strains by manipulation of the gene encoding these proteins is discussed.
Citations
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Journal ArticleDOI
TL;DR: Several regulated non-apoptotic forms of cell death including necroptosis, autophagic cell death, pyroptosis and caspase-independent cell death are discussed, outlining what the authors know about their mechanism, potential roles in vivo and define outstanding questions.
Abstract: Regulated, programmed cell death is crucial for all multicellular organisms. Cell death is essential in many processes, including tissue sculpting during embryogenesis, development of the immune system and destruction of damaged cells. The best-studied form of programmed cell death is apoptosis, a process that requires activation of caspase proteases. Recently it has been appreciated that various non-apoptotic forms of cell death also exist, such as necroptosis and pyroptosis. These non-apoptotic cell death modalities can be either triggered independently of apoptosis or are engaged should apoptosis fail to execute. In this Commentary, we discuss several regulated non-apoptotic forms of cell death including necroptosis, autophagic cell death, pyroptosis and caspase-independent cell death. We outline what we know about their mechanism, potential roles in vivo and define outstanding questions. Finally, we review data arguing that the means by which a cell dies actually matters, focusing our discussion on inflammatory aspects of cell death.

316 citations


Cites background from "Vaccinia virus immune evasion: mech..."

  • ...Many viruses, in particular large doublestranded DNA (dsDNA) viruses, such as vaccinia virus, encode inhibitors of apoptosis (Smith et al., 2013)....

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01 Jan 2016
TL;DR: A live vaccine using recombinant vaccinia viruses has been constructed for both hepatitis B and herpes simplex as mentioned in this paper, which can be used to immunize mice against live HSV-gD.
Abstract: Potential live vaccines using recombinant vaccinia viruses have been constructed for both hepatitis B and herpes simplex. These recombinant vaccinia viruses express cloned genes of the hepatitis B virus surface antigen (HBsAg) or the glycoprotein D from herpes simplex virus (HSV-gD). The HBsAg synthesized in vitro under the regulation of vaccin- ia virus is secreted from infected cells as a particle of -22 nm diameter with a density of 1.2 g/ml as determined on CsCl gradients. Inoculation of rabbits with the recombinant vaccin- ia virus that expresses the HBsAg elicits the production of high-titered antibodies. Synthesis of the HSV-gD was detected in tissue culture by radioimmunoassay on unfixed cells, sug- gesting that the HSV-gD synthesized by the recombinant vac- cinia virus is membrane associated. Inoculation of rabbits with the recombinant vaccinia virus expressing HSV-gD resulted in the production of antibodies that reacted with authentic HSV- gD as detected by radioimmunoassay. Furthermore, the anti- serum was shown by plaque-reduction assay to neutralize the infectivity of herpes simplex virus. Immunization of mice with the vaccinia recombinant expressing HSV-gD gave complete protection on subsequent challenge with lethal doses of live herpes simplex virus.

255 citations

Journal ArticleDOI
TL;DR: It is shown that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGas and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses.
Abstract: Many human cells can sense the presence of exogenous DNA during infection though the cytosolic DNA receptor cyclic GMP-AMP synthase (cGAS), which produces the second messenger cyclic GMP-AMP (cGAMP). Other putative DNA receptors have been described, but whether their functions are redundant, tissue-specific or integrated in the cGAS-cGAMP pathway is unclear. Here we show that interferon-γ inducible protein 16 (IFI16) cooperates with cGAS during DNA sensing in human keratinocytes, as both cGAS and IFI16 are required for the full activation of an innate immune response to exogenous DNA and DNA viruses. IFI16 is also required for the cGAMP-induced activation of STING, and interacts with STING to promote STING phosphorylation and translocation. We propose that the two DNA sensors IFI16 and cGAS cooperate to prevent the spurious activation of the type I interferon response.

238 citations

Book ChapterDOI
TL;DR: Current knowledge about MVA as a unique strain of vaccinia virus, and the prospects of exploiting this virus as research tool in poxvirus biology or as safe viral vector vaccine to challenge existing and future bottlenecks in vaccinology are summarized.
Abstract: Safety tested Modified Vaccinia virus Ankara (MVA) is licensed as third-generation vaccine against smallpox and serves as a potent vector system for development of new candidate vaccines against infectious diseases and cancer. Historically, MVA was developed by serial tissue culture passage in primary chicken cells of vaccinia virus strain Ankara, and clinically used to avoid the undesirable side effects of conventional smallpox vaccination. Adapted to growth in avian cells MVA lost the ability to replicate in mammalian hosts and lacks many of the genes orthopoxviruses use to conquer their host (cell) environment. As a biologically well-characterized mutant virus, MVA facilitates fundamental research to elucidate the functions of poxvirus host-interaction factors. As extremely safe viral vectors MVA vaccines have been found immunogenic and protective in various preclinical infection models. Multiple recombinant MVA currently undergo clinical testing for vaccination against human immunodeficiency viruses, Mycobacterium tuberculosis or Plasmodium falciparum. The versatility of the MVA vector vaccine platform is readily demonstrated by the swift development of experimental vaccines for immunization against emerging infections such as the Middle East Respiratory Syndrome. Recent advances include promising results from the clinical testing of recombinant MVA-producing antigens of highly pathogenic avian influenza virus H5N1 or Ebola virus. This review summarizes our current knowledge about MVA as a unique strain of vaccinia virus, and discusses the prospects of exploiting this virus as research tool in poxvirus biology or as safe viral vector vaccine to challenge existing and future bottlenecks in vaccinology.

195 citations


Cites background from "Vaccinia virus immune evasion: mech..."

  • ...VACV encodes an impressive variety of intracellular virus proteins that can inhibit the host signaling pathways for NF-kB and IRF-3 (for review, see Smith et al., 2013)....

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  • ...VACV can efficiently antagonize the activity of interferons (IFNs), cytokines, chemokines, and innate immune signaling (for review, see Smith et al., 2013)....

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Journal ArticleDOI
TL;DR: 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 is summarized and some perspectives regarding the development of next generation VV vectors for use as cancer therapeutics are offered.
Abstract: 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.

163 citations

References
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Journal ArticleDOI
10 May 1996-Science
TL;DR: A cofactor for HIV-1 (human immunodeficiency virus-type 1) fusion and entry was identified with the use of a novel functional complementary DNA (cDNA) cloning strategy that is a putative G protein-coupled receptor with seven transmembrane segments.
Abstract: A cofactor for HIV-1 (human immunodeficiency virus-type 1) fusion and entry was identified with the use of a novel functional complementary DNA (cDNA) cloning strategy. This protein, designated “fusin,” is a putative G protein-coupled receptor with seven transmembrane segments. Recombinant fusin enabled CD4-expressing nonhuman cell types to support HIV-1 Env-mediated cell fusion and HIV-1 infection. Antibodies to fusin blocked cell fusion and infection with normal CD4-positive human target cells. Fusin messenger RNA levels correlated with HIV-1 permissiveness in diverse human cell types. Fusin acted preferentially for T cell line-tropic isolates, in comparison to its activity with macrophage-tropic HIV-1 isolates.

4,231 citations


"Vaccinia virus immune evasion: mech..." refers methods in this paper

  • ...Apart from the use of recombinant VACVs as live vaccines, these viruses are valuable research tools that have been used, for instance, to identify which virus antigens are recognized by CTLs (Yewdell et al., 1985; Bennink et al., 1986, 1987; McMichael et al., 1986; Osman et al., 1999) and to identify the human immunodeficiency virus (HIV) co-receptor fusin (CXCR4) (Feng et al., 1996)....

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  • ...…tools that have been used, for instance, to identify which virus antigens are recognized by CTLs (Yewdell et al., 1985; Bennink et al., 1986, 1987; McMichael et al., 1986; Osman et al., 1999) and to identify the human immunodeficiency virus (HIV) co-receptor fusin (CXCR4) (Feng et al., 1996)....

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Journal Article
TL;DR: Fusin this article is a putative G protein-coupled receptor with seven transmembrane segments, which enabled CD4-expressing nonhuman cell types to support HIV-1 Env-mediated cell fusion and infection.
Abstract: A cofactor for HIV-1 (human immunodeficiency virus-type 1) fusion and entry was identified with the use of a novel functional complementary DNA (cDNA) cloning strategy. This protein, designated "fusin," is a putative G protein-coupled receptor with seven transmembrane segments. Recombinant fusin enabled CD4-expressing nonhuman cell types to support HIV-1 Env-mediated cell fusion and HIV-1 infection. Antibodies to fusin blocked cell fusion and infection with normal CD4-positive human target cells. Fusin messenger RNA levels correlated with HIV-1 permissiveness in diverse human cell types. Fusin acted preferentially for T cell line-tropic isolates, in comparison to its activity with macrophage-tropic HIV-1 isolates.

4,010 citations

Journal ArticleDOI
23 Feb 2001-Cell
TL;DR: The authors regret the inability to cite all of the primary literature contributing to this review due to length considerations, but wish to thank F. Chan, T. Migone, and J. Wang for insightful comments on the manuscript.

3,756 citations


"Vaccinia virus immune evasion: mech..." refers background in this paper

  • ...TNF-a is the most studied member, and has been implicated in tumour regression, rheumatoid arthritis, septic shock and cachexia (Locksley et al., 2001)....

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Journal ArticleDOI
TL;DR: During a study of the interference produced by heat-inactivated influenza virus with the growth of live virus in fragments of chick chorio-allantoic membrane it was found that following incubation of heated virus with membrane a new factor was released.
Abstract: During a study of the interference produced by heat-inactivated influenza virus with the growth of live virus in fragments of chick chorio-allantoic membrane it was found that following incubation of heated virus with membrane a new factor was released. This factor, recognized by its ability to induce interference in fresh pieces of chorio-allantoic membrane, was called interferon. Following a lag phase interferon was first detected in the membranes after 3 h incubation and thereafter it was released into the surrounding fluid.

2,849 citations

Journal ArticleDOI
TL;DR: The structure, function, and ligand specificity of the receptors responsible for NK cell recognition are reviewed and the role of EMT inNK cell recognition is reviewed.
Abstract: The integrated processing of signals transduced by activating and inhibitory cell surface receptors regulates NK cell effector functions. Here, I review the structure, function, and ligand specificity of the receptors responsible for NK cell recognition.

2,724 citations


"Vaccinia virus immune evasion: mech..." refers background in this paper

  • ...NK cell activation depends on cytokines such as IFN-a, IFN-b, IL-12 and IL-18 but is mostly regulated by a repertoire of activating and inhibitory receptors that integrate signals emanating from the surface of target cells (Lanier, 2005)....

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  • ...In contrast, CD16, NKG2D and the natural cytotoxicity receptors NKp46, NKp44 and NKp30 are mostly involved in the activation of NK cells (Lanier, 2005)....

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