DELAYED ACTIVATION OF ALTERED FUSION GLYCOPROTEIN IN A CHRONIC MEASLES-VIRUS VARIANT THAT CAUSES SUBACUTE SCLEROSING PANENCEPHALITIS

We compared the intracellular processing of the fusion (F) glycoprotei ns of an acute measles virus (MV) Nagahata strain and its relative Bik en strain that caused subacute sclerosing panencephalitis (SSPE). Naga hata strain synthesizes a precursor F-0 which acquires three asparagin e (N)-linked oligosaccharide chains sequentially in 1 h. One oligosacc haride chain on the partially glycosylated F-0 is less accessible to e ndo-beta-N-acetylglucosaminidase H (endo-H) but becomes accessible as the protein becomes fully glycosylated, suggesting a protein conformat ional change. Biken strain SSPE virus synthesizes a similarly glycosyl ated F-0. However, one oligosaccharide chain on the Biken F-0 remains less accessible to endo-a even after the protein is fully glycosylated . The Nagahata F-0 is cleaved into the F-0 and F-0 subunits with a hal f life of 1 h. The Biken F-0 is cleaved with a half life of 4 h. We cl oned the F genes of Nagahata and Biken strains and showed by transfect ion that the defect causing delayed cleavage of F-0 resides in the Bik en F gene. Sequence analysis predicts a mutation in the cleavage recog nition sequence, a truncated carboxyl-terminus, and multiple mutations in F-1 of the Biken F protein. Expression of chimeric F genes showed the mutated cleavage recognition sequence and the carboxyl-terminal tr uncation do not delay cleavage of F-0. Instead, delayed F-0 cleavage i s due to multiple mutations in the extracellular domain of F-1, and fo ur amino acid substitutions near the transmembrane region impair endo- H access to the oligosaccharide chain. These results provide detailed information on the normal maturation process of the F protein of MV an d additional clues to the mechanisms of MV persistence in the CNS.