Cell fusion by the envelope glycoproteins of persistent measles viruses which caused lethal human brain disease

Abstract

Measles virus (MV) rarely induces lethal diseases of the human central nervous system characterized by reduced expression of the viral envelope proteins and by lack of viral budding. The MV envelope contains two integral membrane proteins, termed fusion (F) protein and hemagglutinin (H) protein, and a membraneassociated matrix (M) protein. Previously, analysis of MV genes from autopsy material indicated that the M protein and the F protein intracellular domain are often drastically altered by mutations. Here, we present evidence that truncation of the F protein intracellular domain does not impair fusion function, and we suggest that this alteration interferes with viral budding. Unexpectedly, certain combinations of functional F and H proteins were unable to induce syncytium formation, an observation suggesting that specific F-H protein interactions are required for cell fusion. We also found that three of four H proteins of persistent MVs are defective in intracellular transport, oligosaccharide modification, dimerization, and fusion helper function. Thus, MVs replicating in the brain at the terminal stage of infection are typically defective in M protein and in the two integral membrane proteins. Whereas the M protein appears dispensable altogether, partial preservation of F-protein function and H-protein function seems to be required, presumably to allow local cell fusion. Certain subtle alterations of the F and H proteins may be instrumental for disease development.

Sequence and structure alignment of Paramyxoviridae attachment proteins and discovery of enzymatic activity for a morbillivirus hemagglutinin

“…Alternatively, the archevirus possessed just one membrane protein, the fusion protein. For its proper function, the introduced neuraminidase acquired several characteristics as mentioned above: a transmembrane region and a tetrameric organization, cystine bridges, and an extension of the neuraminidase head to lift it to the same height as the other membrane protein with which it evolved a probable cooperation as is shown for some of the Paramyxoviridae (3,5,13,22,52). On the basis of the low overall amino acid homology between influenza virus N and Paramyxoviridae HN and H, and especially the divergence in cystine bridge connection, it is likely that influenza virus and Paramyxoviridae neuraminidases are not evolutionary related.…”

“…Furthermore, a type-specific functional interaction between F and HN of some paramyxoviruses is required (3,13,22,52). Similarly, a specific interaction is proposed for F and H of a morbillivirus (5).…”

Cell entry by measles virus: long hybrid receptors uncouple binding from membrane fusion

“…In measles virus (MV), as in other paramyxoviruses, both the fusion (F) protein and hemagglutinin (H) are required for fusion (9,46). These proteins are organized on the viral surface in a regular array of tightly packed spikes, H tetramers, and F trimers (29,32,37).…”

Localization of monoclonal antibody epitopes and functional domains in the hemagglutinin protein of measles virus

“…The F protein mediates syncytium formation, which facilitates cell-to-cell spread and is the major cytopathic effect of MV. A specific interaction of the H protein in cell fusion has been suggested, as both MV glycoproteins are often required for fusion activity in expression systems (3,15,34). The most obvious contribution of the H protein to the fusion process is its ability to mediate attachment to cellular receptors.…”