Nectin-4 Interactions Govern Measles Virus Virulence in a New Model of Pathogenesis, the Squirrel Monkey (Saimiri sciureus).

In addition to humans, only certain nonhuman primates are naturally susceptible to measles virus (MeV) infection. Disease severity is species dependent, ranging from mild to moderate for macaques to severe and even lethal for certain New World monkey species. To investigate if squirrel monkeys (), which are reported to develop a course of disease similar to humans, may be better suited than macaques for the identification of virulence determinants or the evaluation of therapeutics, we infected them with a green fluorescent protein-expressing MeV.

Measles virus entry through the signaling lymphocyte activation molecule governs efficacy of mantle cell lymphoma radiovirotherapy.

We developed here a vaccine-identical measles virus (MV) as an oncolytic agent against mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin's lymphoma that is difficult to cure but radiosensitive. We armed the virus with the sodium-iodide symporter, which concentrates iodide within infected cells enabling noninvasive imaging and combination radiovirotherapy. Through high-resolution in vivo and ex vivo imaging, we visualized the spread of infections in primary and metastatic tumors for over 2 weeks after therapy, documenting homogeneous virus seeding and spread restricted to perfused tissue.

Nectin-4-dependent measles virus spread to the cynomolgus monkey tracheal epithelium: role of infected immune cells infiltrating the lamina propria.

After the contagion measles virus (MV) crosses the respiratory epithelium within myeloid cells that express the primary receptor signaling lymphocytic activation molecule (SLAM), it replicates briskly in SLAM-expressing cells in lymphatic organs. Later, the infection spreads to epithelia expressing nectin-4, an adherens junction protein expressed preferentially in the trachea, but how it gets there is not understood. To characterize the mechanisms of spread, we infected groups of 5 or 6 cynomolgus monkeys (Macaca fascicularis) with either a wild-type MV or its "N4-blind" derivative, which is unable to enter nectin-4-expressing cells because of the targeted mutation of two hemagglutinin residues.

Broadly neutralizing immune responses against hepatitis C virus induced by vectored measles viruses and a recombinant envelope protein booster.

Hepatitis C virus (HCV) infection remains a serious public health problem worldwide. Treatments are limited, and no preventive vaccine is available. Toward developing an HCV vaccine, we engineered two recombinant measles viruses (MVs) expressing structural proteins from the prototypic HCV subtype 1a strain H77.

Adherens junction protein nectin-4 is the epithelial receptor for measles virus.

Measles virus is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths. Although it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to infect initially macrophages and dendritic cells of the airways using signalling lymphocytic activation molecule family member 1 (SLAMF1; also called CD150) as a receptor. These cells then cross the respiratory epithelium and transport the infection to lymphatic organs where measles virus replicates vigorously.

Envelope-chimeric entry-targeted measles virus escapes neutralization and achieves oncolysis.

Measles virus (MV) is a promising vector for cancer therapy and multivalent vaccination, but high prevalence of pre-existing neutralizing antibodies may reduce therapeutic efficacy, particularly following systemic administration. MV has only one serotype, but here we show that its envelope glycoproteins can be exchanged with those of the closely related canine distemper virus (CDV), generating a chimeric virus capable of escaping neutralization. To target its entry, we displayed on the CDV attachment protein a single-chain antibody specific for a designated receptor.

MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism.

Oncolytic measles viruses (MV) derived from the live attenuated vaccine strain have been engineered for increased tumor-cell specificity, and are currently under investigation in clinical trials including a phase I study for glioblastoma multiforme (GBM). Recent preclinical studies have shown that the cellular tropism of several viruses can be controlled by inserting microRNA-target sequences into their genomes, thereby inhibiting spread in tissues expressing cognate microRNAs. Since neuron-specific microRNA-7 is downregulated in gliomas but highly expressed in normal brain tissue, we engineered a microRNA-sensitive virus containing target sites for microRNA-7 in the 3'-untranslated region of the viral fusion gene.

Measles virus infection of alveolar macrophages and dendritic cells precedes spread to lymphatic organs in transgenic mice expressing human signaling lymphocytic activation molecule (SLAM, CD150).

Recent studies of primate models suggest that wild-type measles virus (MV) infects immune cells located in the airways before spreading systemically, but the identity of these cells is unknown. To identify cells supporting primary MV infection, we took advantage of mice expressing the MV receptor human signaling lymphocyte activation molecule (SLAM, CD150) with human-like tissue specificity. We infected these mice intranasally (IN) with a wild-type MV expressing green fluorescent protein.

Lymphoma chemovirotherapy: CD20-targeted and convertase-armed measles virus can synergize with fludarabine.

Combination chemotherapy regimen incorporating CD20 antibodies are commonly used in the treatment of CD20-positive non-Hodgkin's lymphoma (NHL). Fludarabine phosphate (F-araAMP), cyclophosphamide, and CD20 antibodies (Rituximab) constitute the FCR regimen for treating selected NHL, including aggressive mantle cell lymphoma (MCL). As an alternative to the CD20 antibody, we generated a CD20-targeted measles virus (MV)-based vector.

An immunocompetent murine model for oncolysis with an armed and targeted measles virus.

An immunocompetent model is required to test therapeutic regimens for clinical trials with the oncolytic measles virus (MV). Toward developing this model, a retargeted MV that enters murine colon adenocarcinoma cells forming tumors in syngeneic C57BL/6 mice was generated. Since MV infection tends to be less efficient in murine than in human cells, the targeted virus was also armed with the prodrug convertase, purine nucleoside phosphorylase (PNP), and named MV-PNP-antiCEA.

Oncolytic efficacy and enhanced safety of measles virus activated by tumor-secreted matrix metalloproteinases.

Cancer cells secrete matrix metalloproteinases (MMP) that degrade the extracellular matrix and are responsible for some hallmarks of malignant cancer. Many viruses, including a few currently used in oncolytic virotherapy clinical trials, depend on intracellular proteases to process their proteins and activate their particles. We show here for measles virus (MV) that particle activation can be made dependent of proteases secreted by cancer cells.

Oncolytic activities of approved mumps and measles vaccines for therapy of ovarian cancer.

Oncolytic viruses are promising cytoreductive agents for cancer treatment but extensive human testing will be required before they are made commercially available. Here, we investigated the oncolytic potential of two commercially available live attenuated vaccines, Moraten measles and Jeryl-Lynn mumps, in a murine model of intraperitoneal human ovarian cancer and compared their efficacies against a recombinant oncolytic measles virus (MV-CEA) that is being tested in a phase I clinical trial. The common feature of these viruses is that they express hemagglutinin and fusion therapeutic proteins that can induce extensive fusion of the infected cell with its neighbors, resulting in death of the cell monolayer.

Biodistribution of oncolytic measles virus after intraperitoneal administration into Ifnar-CD46Ge transgenic mice.

In support of a proposed phase I clinical trial, we studied the biodistribution of virus-infected cells after intraperitoneal administration of oncolytic measles viruses to alpha/beta interferon-defective mice expressing human CD46 with human-like tissue specificity. Various marker genes were employed, and green fluorescent protein proved to be most informative. Mesothelium and ovarian surface epithelium were remarkably resistant to infection, but infected peritoneal macrophages were present in abundance both in peritoneal lavage fluid and in the greater omentum, where they were heavily concentrated in "milky spots".