Early-stage clinical trials of oncolytic virotherapy have reported the safety of several virus platforms, and viruses from three families have progressed to advanced efficacy trials. In addition, ...preclinical studies have established proof-of-principle for many new genetic engineering strategies. Thus, the virotherapy field now has available a diverse collection of viruses that are equipped to address unmet clinical needs owing to improved systemic administration, greater tumour specificity and enhanced oncolytic efficacy. The current key challenge for the field is to develop viruses that replicate with greater efficiency within tumours while achieving therapeutic synergy with currently available treatments.
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Other fast lanes, while forming below the cell surface, push released particles to “surf” towards noninfected cells 7. ...some viruses take advantage of structures built by circulating cells to ...communicate, such as the immunological synapse, to spread more rapidly 2. ...the lowest portion of the tract that lacks cilia and mucus is safeguarded by macrophages that destroy particles. ...mechanisms that allow viral spread within the airway epithelia without particle release would be highly advantageous, and recent studies suggest that some respiratory viruses have indeed developed alternative means of spread. ...the complete assembly of virions is not needed, and direct cell-to-cell transfer of viral genetic material, proteins, nucleocapsids, or replication bodies is most likely occurring. ...disruption of intercellular extensions or intercellular pores by different means leads to reduced and/or less efficient viral spread.
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Research in the last decade has uncovered many new paramyxoviruses, airborne agents that cause epidemic diseases in animals including humans. Most paramyxoviruses enter epithelial cells of the airway ...using sialic acid as a receptor and cause only mild disease. However, others cross the epithelial barrier and cause more severe disease. For some of these viruses, the host receptors have been identified, and the mechanisms of cell entry have been elucidated. The tetrameric attachment proteins of paramyxoviruses have vastly different binding affinities for their cognate receptors, which they contact through different binding surfaces. Nevertheless, all input signals are converted to the same output: conformational changes that trigger refolding of trimeric fusion proteins and membrane fusion. Experiments with selectively receptor-blinded viruses inoculated into their natural hosts have provided insights into tropism, identifying the cells and tissues that support growth and revealing the mechanisms of pathogenesis. These analyses also shed light on diabolically elegant mechanisms used by morbilliviruses, including the measles virus, to promote massive amplification within the host, followed by efficient aerosolization and rapid spread through host populations. In another paradigm of receptor-facilitated severe disease, henipaviruses, including Nipah and Hendra viruses, use different members of one protein family to cause zoonoses. Specific properties of different paramyxoviruses, like neurotoxicity and immunosuppression, are now understood in the light of receptor specificity. We propose that research on the specific receptors for several newly identified members of the Paramyxoviridae family that may not bind sialic acid is needed to anticipate their zoonotic potential and to generate effective vaccines and antiviral compounds.
Upon infection, morbilliviruses such as measles virus, rinderpest virus, and canine distemper virus (CDV) initially target immune cells via the signaling lymphocyte activation molecule (SLAM) before ...spreading to respiratory epithelia through the adherens junction protein nectin-4. However, the roles of these receptors in transmission from infected to naive hosts have not yet been formally tested. To experimentally addressing this question, we established a model of CDV contact transmission between ferrets. We show here that transmission of wild-type CDV sometimes precedes the onset of clinical disease. In contrast, transmission was not observed in most animals infected with SLAM- or nectin-4-blind CDVs, even though all animals infected with the nectin-4-blind virus developed sustained viremia. There was an unexpected case of transmission of a nectin-4-blind virus, possibly due to biting. Another unprecedented event was transient viremia in an infection with a SLAM-blind virus. We identified three compensatory mutations within or near the SLAM-binding surface of the attachment protein. A recombinant CDV expressing the mutated attachment protein regained the ability to infect ferret lymphocytes
, but its replication was not as efficient as that of wild-type CDV. Ferrets infected with this virus developed transient viremia and fever, but there was no transmission to naive contacts. Our study supports the importance of epithelial cell infection and of sequential CDV H protein interactions first with SLAM and then nectin-4 receptors for transmission to naive hosts. It also highlights the
selection pressure on the H protein interactions with SLAM.
Morbilliviruses such as measles virus, rinderpest virus, and canine distemper virus (CDV) are highly contagious. Despite extensive knowledge of how morbilliviruses interact with their receptors, little is known about how those interactions influence viral transmission to naive hosts. In a ferret model of CDV contact transmission, we showed that sequential use of the signaling lymphocytic activation molecule (SLAM) and nectin-4 receptors is essential for transmission. In one animal infected with a SLAM-blind CDV, we documented mild viremia due to the acquisition of three compensatory mutations within or near the SLAM-binding surface. The interaction, however, was not sufficient to cause disease or sustain transmission to naive contacts. This work confirms the sequential roles of SLAM and nectin-4 in morbillivirus transmission and highlights the selective pressure directed toward productive interactions with SLAM.
...host immunosuppression with cyclophosphamide prior to virus administration enhances oncolytic efficacy, likely by suppressing host innate and adaptive immunity and temporarily favoring virus ...replication. ...the first oncolytic virus approved as a cancer drug has been administered to thousand of patients in China 22, multiple viruses with improved oncolytic properties are currently being tested in well-controlled clinical trials, and the next generation of targeted viruses capable of integrating chemo- and radiotherapies is approaching clinical testing.
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About the Authors: Roberto Cattaneo * E-mail: Cattaneo.Roberto@mayo.edu Affiliation: Department of Molecular Medicine and Virology and Gene Therapy Graduate School track, Mayo Clinic, Rochester, ...Minnesota, United States of America Stephen J. Russell Affiliation: Department of Molecular Medicine and Virology and Gene Therapy Graduate School track, Mayo Clinic, Rochester, Minnesota, United States of AmericaCitation: Cattaneo R, Russell SJ (2017) How to develop viruses into anticancer weapons. Competing interests: SJR is a scientific cofounder, equity stakeholder, board member and serves as CEO at Vyriad, a company that is developing oncolytic measles viruses for cancer therapy. In the mid-20th century, the principle of virus attenuation through adaptation to unnatural hosts was extended to cultured cells: cells from different species were used to select viruses with multiple mutations, reducing replication speed and allowing the immune system to control viral infection. ...subunit vaccines are proving to be effective against virus-induced cancers, preventing hepatitis B virus-induced hepatocellular carcinoma and human papilloma virus-induced cervical cancer 2, 4. Intentional transmission of virus infections was then pursued in a range of cancer types using several different virus isolates (most notably West Nile, mumps, and adenovirus) and led to definite tumor regressions but sometimes also to fatal encephalitis, as with West Nile virus in immunosuppressed lymphoma patients 8. ...the vaccine lineage-based measles virus (MeV) platform we have developed can enter many cell types through the ubiquitously expressed protein CD46, while future clinical trials may be based on viruses with targeted tropism. ...targeted cell entry and cell-cell fusion: the two-protein MeV...
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The epithelium is a highly organized type of animal tissue. Except for blood and lymph vessels, epithelial cells cover the body, line its cavities in single or stratified layers and support exchange ...between compartments. In addition, epithelia offer to the body a barrier to pathogen invasion. To transit through or to replicate in epithelia, viruses have to face several obstacles, starting from cilia and glycocalyx where they can be neutralized by secreted immunoglobulins. Tight junctions and adherens junctions also prevent viruses to cross the epithelial barrier. However, viruses have developed multiple strategies to blaze their path through the epithelium by utilizing components of cell–cell adhesion structures as receptors. In this Commentary, we discuss how viruses take advantage of the apical junction complex to spread. Whereas some viruses quickly disrupt epithelium integrity, others carefully preserve it and use cell adhesion proteins and their cytoskeletal connections to rapidly spread laterally. This is exemplified by the hidden transmission of enveloped viruses that use nectins as receptors. Finally, several viruses that replicate preferentially in cancer cells are currently used as experimental cancer therapeutics. Remarkably, these viruses use cell adhesion molecules as receptors, probably because--to reach tumors and metastases--ncolytic viruses must efficiently traverse or break epithelia.
Measles virus (MeV) is dual-tropic: it replicates first in lymphatic tissues and then in epithelial cells. This switch in tropism raises the question of whether, and how, intra-host evolution occurs. ...Towards addressing this question, we adapted MeV either to lymphocytic (Granta-519) or epithelial (H358) cells. We also passaged it consecutively in both human cell lines. Since passaged MeV had different replication kinetics, we sought to investigate the underlying genetic mechanisms of growth differences by performing deep-sequencing analyses. Lymphocytic adaptation reproducibly resulted in accumulation of variants mapping within an 11-nucleotide sequence located in the middle of the phosphoprotein (P) gene. This sequence mediates polymerase slippage and addition of a pseudo-templated guanosine to the P mRNA. This form of co-transcriptional RNA editing results in expression of an interferon antagonist, named V, in place of a polymerase co-factor, named P. We show that lymphocytic-adapted MeV indeed produce minimal amounts of edited transcripts and V protein. In contrast, parental and epithelial-adapted MeV produce similar levels of edited and non-edited transcripts, and of V and P proteins. Raji, another lymphocytic cell line, also positively selects V-deficient MeV genomes. On the other hand, in epithelial cells V-competent MeV genomes rapidly out-compete the V-deficient variants. To characterize the mechanisms of genome re-equilibration we rescued four recombinant MeV carrying individual editing site-proximal mutations. Three mutations interfered with RNA editing, resulting in almost exclusive P protein expression. The fourth preserved RNA editing and a standard P-to-V protein expression ratio. However, it altered a histidine involved in Zn2+ binding, inactivating V function. Thus, the lymphocytic environment favors replication of V-deficient MeV, while the epithelial environment has the opposite effect, resulting in rapid and thorough cyclical quasispecies re-equilibration. Analogous processes may occur in natural infections with other dual-tropic RNA viruses.
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Particles of many paramyxoviruses include small amounts of proteins with a molecular weight of about 20 kDa. These proteins, termed "C", are basic, have low amino acid homology and some secondary ...structure conservation. C proteins are encoded in alternative reading frames of the phosphoprotein gene. Some viruses express nested sets of C proteins that exert their functions in different locations: In the nucleus, they interfere with cellular transcription factors that elicit innate immune responses; in the cytoplasm, they associate with viral ribonucleocapsids and control polymerase processivity and orderly replication, thereby minimizing the activation of innate immunity. In addition, certain C proteins can directly bind to, and interfere with the function of, several cytoplasmic proteins required for interferon induction, interferon signaling and inflammation. Some C proteins are also required for efficient virus particle assembly and budding. C-deficient viruses can be grown in certain transformed cell lines but are not pathogenic in natural hosts. C proteins affect the same host functions as other phosphoprotein gene-encoded proteins named V but use different strategies for this purpose. Multiple independent systems to counteract host defenses may ensure efficient immune evasion and facilitate virus adaptation to new hosts and tissue environments.
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