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      The Tumor-Associated Marker, PVRL4 (Nectin-4), is the Epithelial Receptor for Morbilliviruses

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          Abstract

          PVRL4 (nectin-4) was recently identified as the epithelial receptor for members of the Morbillivirus genus, including measles virus, canine distemper virus and peste des petits ruminants virus. Here, we describe the role of PVRL4 in morbillivirus pathogenesis and its promising use in cancer therapies. This discovery establishes a new paradigm for the spread of virus from lymphocytes to airway epithelial cells and its subsequent release into the environment. Measles virus vaccine strains have emerged as a promising oncolytic platform for cancer therapy in the last ten years. Given that PVRL4 is a well-known tumor-associated marker for several adenocarcinoma (lung, breast and ovary), the measles virus could potentially be used to specifically target, infect and destroy cancers expressing PVRL4.

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          Adherens junction protein nectin-4 (PVRL4) is the epithelial receptor for measles virus

          Measles (MV) is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths 1,2 . While it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to initially infect macrophages and dendritic cells of the airways using the signaling lymphocytic activation molecule (SLAM, CD150) as receptor 3-6 . These cells then cross the respiratory epithelium and ferry the infection to lymphatic organs where MV replicates vigorously 7 . How and where the virus crosses back into the airways has remained unknown. Based on functional analyses of surface proteins preferentially expressed on virus-permissive epithelial cell lines, we identified nectin-4 8 (poliovirus-receptor-like-4) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains MV entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is down-regulated in infected epithelial cells, including those of macaque tracheas. While other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that MV targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer 9-11 , which has implications for ongoing MV-based clinical trials of oncolysis 12 .
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            Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily.

            Restriction of poliovirus replication to a few sites in the infected primate host appears to be controlled by the expression of viral receptors. To learn more about these binding sites and their role in viral tissue tropism, cDNA clones encoding functional poliovirus receptors were isolated. The predicted amino acid sequence reveals that the human poliovirus receptor is an integral membrane protein with the conserved amino acids and domain structure characteristic of members of the immunoglobulin superfamily. Northern hybridization analysis indicates that poliovirus receptor transcripts are expressed in a wide range of human tissues, in contrast to the limited expression of virus binding sites, which suggests that additional factors or modifications of the receptor protein are required to permit poliovirus attachment.
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              Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.

              Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.
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                Author and article information

                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                02 June 2014
                June 2014
                : 6
                : 6
                : 2268-2286
                Affiliations
                [1 ]The Department of Microbiology and Immunology, Dalhousie University, Halifax, B3H 1X5 NS, Canada; E-Mails: sebastien.delpeut@ 123456dal.ca (S.D.); noycer@ 123456dal.ca (R.S.N.)
                [2 ]IWK Health Centre, Canadian Center for Vaccinology, Goldbloom Pavilion, Halifax, B3H 1X5 NS, Canada
                [3 ]The Department of Pediatrics, Dalhousie University, Halifax, B3K 6R8 NS, Canada
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ]Author to whom correspondence should be addressed; E-Mail: chris.richardson@ 123456dal.ca ; Tel.: 902-494-6876; Fax: 902-470-7232.
                Article
                viruses-06-02268
                10.3390/v6062268
                4074928
                24892636
                481c4795-dedf-43da-80ed-3cee64219833
                © 2014 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 19 March 2014
                : 14 May 2014
                : 15 May 2014
                Categories
                Review

                Microbiology & Virology
                morbillivirus,measles virus,canine distemper virus,peste des petits ruminants virus,nectin-4,pvrl4,epithelial receptor,cancer

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