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      Poxvirus tropism

      review-article
      Nature Reviews. Microbiology
      Nature Publishing Group UK

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          Abstract

          Despite the success of the WHO-led smallpox eradication programme a quarter of a century ago, there remains considerable fear that variola virus, or other related pathogenic poxviruses such as monkeypox, could re-emerge and spread disease in the human population. Even today, we are still mostly ignorant about why most poxvirus infections of vertebrate hosts show strict species specificity, or how zoonotic poxvirus infections occur when poxviruses occasionally leap into novel host species. Poxvirus tropism at the cellular level seems to be regulated by intracellular events downstream of virus binding and entry, rather than at the level of specific host receptors as is the case for many other viruses. This review summarizes our current understanding of poxvirus tropism and host range, and discusses the prospects of exploiting host-restricted poxvirus vectors for vaccines, gene therapy or tissue-targeted oncolytic viral therapies for the treatment of human cancers.

          Key Points

          • Poxvirus host range varies markedly ? some viruses, such as variola and molluscum contagiosum virus (both of which are human-specific), exhibit strict species tropism, whereas others such as cowpox virus are able to infect multiple host species.

          • Members of four of the eight genera of chordopoxviruses can zoonotically infect man. For example, monkeypox virus can cause severe smallpox-like disease in humans that clinically resembles variola virus.

          • The species tropism that is exhibited by many poxviruses in terms of causing disease is frequently quite different from the range of cultured cells that can be infected by these viruses.

          • Specific host-cell receptors do not mediate the distinction between cells that are permissive as opposed to non-permissive for poxvirus infection. Rather, restrictive host cells fail to support the full replication cycle of the infecting poxvirus at a point downstream of binding and entry.

          • A variety of poxviral host-range genes have been identified that contribute to the control of permissive versus non-permissive infection of cultured mammalian cells. The gene products of these host-range genes regulate the ability of the virus to complete its cytoplasmic replication cycle.

          • The development of host-restricted vaccines, like modified vaccinia Ankara (MVA), that do not replicate in humans but that retain potent immunogenicity, will provide safer platforms for recombinant vaccines.

          • Another advance has been the development of poxvirus-based oncolytic vectors that replicate preferentially in human tumour cells.

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          Most cited references182

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          Antiviral actions of interferons.

          C Samuel (2001)
          Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs. Furthermore, advances made while elucidating the IFN system have contributed significantly to our understanding in multiple areas of virology and molecular cell biology, ranging from pathways of signal transduction to the biochemical mechanisms of transcriptional and translational control to the molecular basis of viral pathogenesis. IFNs are approved therapeutics and have moved from the basic research laboratory to the clinic. Among the IFN-induced proteins important in the antiviral actions of IFNs are the RNA-dependent protein kinase (PKR), the 2',5'-oligoadenylate synthetase (OAS) and RNase L, and the Mx protein GTPases. Double-stranded RNA plays a central role in modulating protein phosphorylation and RNA degradation catalyzed by the IFN-inducible PKR kinase and the 2'-5'-oligoadenylate-dependent RNase L, respectively, and also in RNA editing by the IFN-inducible RNA-specific adenosine deaminase (ADAR1). IFN also induces a form of inducible nitric oxide synthase (iNOS2) and the major histocompatibility complex class I and II proteins, all of which play important roles in immune response to infections. Several additional genes whose expression profiles are altered in response to IFN treatment and virus infection have been identified by microarray analyses. The availability of cDNA and genomic clones for many of the components of the IFN system, including IFN-alpha, IFN-beta, and IFN-gamma, their receptors, Jak and Stat and IRF signal transduction components, and proteins such as PKR, 2',5'-OAS, Mx, and ADAR, whose expression is regulated by IFNs, has permitted the generation of mutant proteins, cells that overexpress different forms of the proteins, and animals in which their expression has been disrupted by targeted gene disruption. The use of these IFN system reagents, both in cell culture and in whole animals, continues to provide important contributions to our understanding of the virus-host interaction and cellular antiviral response.
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            The detection of monkeypox in humans in the Western Hemisphere.

            During May and June 2003, an outbreak of febrile illness with vesiculopustular eruptions occurred among persons in the midwestern United States who had had contact with ill pet prairie dogs obtained through a common distributor. Zoonotic transmission of a bacterial or viral pathogen was suspected. We reviewed medical records, conducted interviews and examinations, and collected blood and tissue samples for analysis from 11 patients and one prairie dog. Histopathological and electron-microscopical examinations, microbiologic cultures, and molecular assays were performed to identify the etiologic agent. The initial Wisconsin cases evaluated in this outbreak occurred in five males and six females ranging in age from 3 to 43 years. All patients reported having direct contact with ill prairie dogs before experiencing a febrile illness with skin eruptions. We found immunohistochemical or ultrastructural evidence of poxvirus infection in skin-lesion tissue from four patients. Monkeypox virus was recovered in cell cultures of seven samples from patients and from the prairie dog. The virus was identified by detection of monkeypox-specific DNA sequences in tissues or isolates from six patients and the prairie dog. Epidemiologic investigation suggested that the prairie dogs had been exposed to at least one species of rodent recently imported into the United States from West Africa. Our investigation documents the isolation and identification of monkeypox virus from humans in the Western Hemisphere. Infection of humans was associated with direct contact with ill prairie dogs that were being kept or sold as pets. Copyright 2004 Massachusetts Medical Society
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              Virus entry: molecular mechanisms and biomedical applications

              Key Points Virus entry into animal cells is initiated by attachment to receptors and is followed by important conformational changes of viral proteins, penetration through (non-enveloped viruses) or fusion with (enveloped viruses) cellular membranes. The process ends with transfer of viral genomes inside host cells. Viral proteins mediating entry are very diverse, but many share common three-dimensional structural motifs. Conformational changes in the viral proteins that drive entry are typically initiated by high-affinity interactions with receptors, or changes in pH after receptor binding and internalization. They include formation of coiled-coils in class I fusion proteins, dimer to trimer transitions in class II fusion proteins, movement of capsid proteins in non-enveloped viruses and exposure of membrane destabilizing sequences. Fusion with, or penetration through, cell membranes might involve multimolecular protein complexes and requires structural rearrangements of membrane lipids. Inhibitors of virus entry can prevent virus attachment, or bind to entry intermediates; small organic molecules, peptides, soluble receptors and antibodies are in clinical trials. Six virus-specific polyclonal human immunoglobulins, one monoclonal antibody and one peptide have been approved by the US Food and Drug Administration for clinical use. Viral proteins involved in entry can induce immune responses and be used as vaccine immunogens. Viral entry machineries could be beneficial for human physiology and retargeted for the treatment of cancer and other diseases.
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                Author and article information

                Contributors
                mcfadden@robarts.ca
                Journal
                Nat Rev Microbiol
                Nat. Rev. Microbiol
                Nature Reviews. Microbiology
                Nature Publishing Group UK (London )
                1740-1526
                1740-1534
                2005
                : 3
                : 3
                : 201-213
                Affiliations
                GRID grid.39381.30, ISNI 0000 0004 1936 8884, Department of Microbiology and Immunology, , University of Western Ontario, and Robarts Research Institute, Siebens-Drake Building, Room 133, ; 1400 Western Road, London, N6G 2V4 Ontario Canada
                Article
                BFnrmicro1099
                10.1038/nrmicro1099
                4382915
                15738948
                0280db5b-677f-4735-994b-830376d891de
                © Nature Publishing Group 2005

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2005

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