The Paramyxoviridae are enveloped, non-segmented, negative-strand RNA viruses that include major human pathogens belonging to two subfamilies. The Pneumonvirinae subfamily includes respiratory syncytial virus (RSV) and the metapneumoviruses, while the Paramyxovirinae subfamily includes, amongst others, measles virus (MeV), mumps virus, human parainfluenza viruses (hPIV1-4), and the recently emerged, highly pathogenic henipaviruses Hendra (HeV) and Nipah (NiV). Members of both subfamilies are responsible for significant human morbidity and mortality. MeV, in particular, remains a major cause of childhood mortality worldwide despite the availability of a live-attenuated vaccine.
All paramyxoviruses gain entry into and spread between cells by promoting direct membrane fusion. Membrane merger is mediated by the viral fusion (F) protein, which, like other class I fusion proteins such as influenza HA and HIV env, first forms metastable homo-trimers that require proteolytic activation to gain functionality. Receptor binding by the attachment protein is thought to then trigger major conformational changes in mature F, resulting first in insertion of a hydrophobic domain, the fusion peptide, into the target membrane and ultimately in formation of a fusion pore through juxtapositioning of the F transmembrane domain and fusion peptide in the thermodynamically stable postfusion conformation. Unlike retro- or orthomyxovirus entry, the complexity of the paramyxovirus fusion triggering mechanism is raised to a higher level by the fact that the receptor binding and fusion-promoting functions are contributed by separately encoded envelope glycoproteins. This physical separation of the two functions necessitates a mechanism of posttranslational linkage, which is accomplished through the formation of virus-specific hetero-oligomer complexes between the two proteins. However, the overall organization of functional Paramyxovirinae fusion complexes and the molecular mechanism that links receptor binding with coordinated F protein refolding into the postfusion conformation remain largely unknown.
Structural and Mechanistic Studies of Measles Virus Illuminate Paramyxovirus Entry. (2011) PLoS Pathog 7(6): e1002058. doi:10.1371/journal.ppat.1002058
Measles virus (MeV), a member of the paramyxovirus family of enveloped RNA viruses and one of the most infectious viral pathogens identified, accounts for major pediatric morbidity and mortality worldwide although coordinated efforts to achieve global measles control are in place. Target cell entry is mediated by two viral envelope glycoproteins, the attachment (H) and fusion (F) proteins, which form a complex that achieves merger of the envelope with target cell membranes. Despite continually expanding knowledge of the entry strategies employed by enveloped viruses, our molecular insight into the organization of functional paramyxovirus fusion complexes and the mechanisms by which the receptor binding by the attachment protein triggers the required conformational rearrangements of the fusion protein remain incomplete. Recently reported crystal structures of the MeV attachment protein in complex with its cellular receptors CD46 or SLAM and newly developed functional assays have now illuminated some of the fundamental principles that govern cell entry by this archetype member of the paramyxovirus family. Here, we review these advances in our molecular understanding of MeV entry in the context of diverse entry strategies employed by other members of the paramyxovirus family.
Measles virus (MV) belongs to the genus Morbillivirus of the family Paramyxoviridae. A number of paramyxoviruses inhibit host interferon (IFN) signaling pathways in host immune systems by various mechanisms. Inhibition mechanisms have been described for many paramyxoviruses. Although there are inconsistencies among previous reports concerning MV, it appears that P/V/C proteins interfere with the pathways.
