Mutations in the Fusion Protein of Measles Virus That Confer Resistance to the Membrane Fusion Inhibitors Carbobenzoxy-d-Phe-l-Phe-Gly and 4-Nitro-2-Phenylacetyl Amino-Benzamide.

The inhibitors carbobenzoxy (Z)-d-Phe-l-Phe-Gly (fusion inhibitor peptide [FIP]) and 4-nitro-2-phenylacetyl amino-benzamide (AS-48) have similar efficacies in blocking membrane fusion and syncytium formation mediated by measles virus (MeV). Other homologues, such as Z-d-Phe, are less effective but may act through the same mechanism. In an attempt to map the site of action of these inhibitors, we generated mutant viruses that were resistant to the inhibitory effects of Z-d-Phe-l-Phe-Gly.

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 Enters Breast and Colon Cancer Cell Lines through a PVRL4-Mediated Macropinocytosis Pathway.

Measles virus (MeV) is a member of the family that causes a highly contagious respiratory disease but has emerged as a promising oncolytic platform. Previous studies of MeV entry focused on the identification of cellular receptors. However, the endocytic and trafficking pathways utilized during MeV entry remain poorly described.

The tumor-associated marker, PVRL4 (nectin-4), is the epithelial receptor for morbilliviruses.

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.

The V domain of dog PVRL4 (nectin-4) mediates canine distemper virus entry and virus cell-to-cell spread.

The entry of canine distemper virus (CDV) is a multistep process that involves the attachment of CDV hemagglutinin (H) to its cellular receptor, followed by fusion between virus and cell membranes. Our laboratory recently identified PVRL4 (nectin-4) to be the epithelial receptor for measles and canine distemper viruses. In this study, we demonstrate that the V domain of PVRL4 is critical for CDV entry and virus cell-to-cell spread.

Dog nectin-4 is an epithelial cell receptor for canine distemper virus that facilitates virus entry and syncytia formation.

Canine distemper virus (CDV) was shown to use dog nectin-4 as a receptor to gain entry into epithelial cells. RNA from dog placenta or MDCK kidney cells was isolated and cDNAs were prepared. Two splice variants of dog nectin-4 were identified.

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.

Host factors and measles virus replication.

This review takes a general approach to describing host cell factors that facilitate measles virus (MeV) infection and replication. It relates our current understanding of MeV entry receptors, with emphasis on how these host cell surface proteins contribute to pathogenesis within its host. The roles of SLAM/CD150 lymphocyte receptor and the newly discovered epithelial receptor PVRL4/nectin-4 are highlighted.

L'étude de la maladie de Carré chez ses hôtes naturels : un modèle de pathogenèse morbillivirale.

Morbilliviruses cause a severe and sometimes lethal disease in their respective hosts, which is characterized by a generalized immunosuppression, respiratory and gastro-intestinal clinical signs, and occasional neurological complications. This similarity in the biology of different members of the morbillivirus genus constitutes the basis for the study of canine distemper virus in its natural hosts as a model for the characterization of morbillivirus pathogenesis. In combination with the reverse genetics technology, which allows the production of recombinant viruses carrying specific genetic modifications, this model has made important contributions to our understanding of the mechanisms underlying morbillivirus immunosuppression, dissemination, and neuroinvasion.

Membrane fusion-mediated autophagy induction enhances morbillivirus cell-to-cell spread.

In the context of viral infections, autophagy induction can be beneficial or inhibitory. Within the Paramyxoviridae family, only morbilliviruses have been investigated and are reported to induce autophagy. Here we show that morbilliviruses rapidly induce autophagy and require this induction for efficient cell-to-cell spread.

Mutations abrogating VP35 interaction with double-stranded RNA render Ebola virus avirulent in guinea pigs.

Ebola virus (EBOV) protein VP35 is a double-stranded RNA (dsRNA) binding inhibitor of host interferon (IFN)-alpha/beta responses that also functions as a viral polymerase cofactor. Recent structural studies identified key features, including a central basic patch, required for VP35 dsRNA binding activity. To address the functional significance of these VP35 structural features for EBOV replication and pathogenesis, two point mutations, K319A/R322A, that abrogate VP35 dsRNA binding activity and severely impair its suppression of IFN-alpha/beta production were identified.

Ebolavirus glycoprotein GP masks both its own epitopes and the presence of cellular surface proteins.

Ebolavirus (EBOV) is the etiological agent of a severe hemorrhagic fever with a high mortality rate. The spike glycoprotein (GP) is believed to be one of the major determinants of virus pathogenicity. In this study, we demonstrated the molecular mechanism responsible for the downregulation of surface markers caused by EBOV GP expression.

High risk HPV load estimated by Hybrid Capture II correlates with HPV16 load measured by real-time PCR in cervical smears of HPV16-infected women.

Background: High risk human papillomavirus (HR-HPV) load determined by quantitative methods has already been considered as highly predictive of future development of high grade cervical lesions. Some studies also demonstrated that Hybrid Capture II (HCII) results can be considered as a reflection of HPV DNA load, while others did not. HCI assay, well suited for routine HR-HPV screening, is not especially dedicated for quantitative use.