Evidence that the hypermutated M protein of a subacute sclerosing panencephalitis measles virus actively contributes to the chronic progressive CNS disease.
Subacute sclerosing panencephalitis (SSPE) is a progressive degenerative disease of the brain uniformly leading to death. Although caused by measles virus (MV), the virus recovered from patients with SSPE differs from wild-type MV; biologically SSPE virus is defective and its genome displays a variety of mutations among which biased replacements of many uridine by cytidine resides primarily in the matrix (M) gene. To address the question of whether the SSPE MVs with M mutations are passive in that they are not infectious, cannot spread within the CNS, and basically represent an end-stage result of a progressive infection or alternatively SSPE viruses are infectious, and their mutations enable them to persist and thereby cause a prolonged neurodegenerative disease, we utilized reverse genetics to generate an infectious virus in which the M gene of MV was replaced with the M gene of Biken strain SSPE MV and inoculated the recombinant virus into transgenic mice bearing the MV receptor. Our results indicate that despite biased hypermutations in the M gene, the virus is infectious in vivo and produces a protracted progressive infection with death occurring as long as 30 to 50 days after that caused by MV. In primary neuron cultures, the mutated M protein is not essential for MV replication, prevents colocalization of the viral N with membrane glycoproteins, and is associated with accumulation of nucleocapsids in cells' cytoplasm and nucleus.
Patterson
J B
JB
Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cornu
T I
TI
Redwine
J
J
Dales
S
S
Lewicki
H
H
Holz
A
A
Thomas
D
D
Billeter
M A
MA
Oldstone
M B
MB
D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000821:virology; D019590:Nucleocapsid Proteins / Q000378:metabolism; D013190:SSPE Virus / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D013344:Subacute Sclerosing Panencephalitis / Q000401:mortality / Q000821:virology*; D013347:Subcellular Fractions; D014709:Vero Cells; D014760:Viral Fusion Proteins / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C119679:M protein, SSPE virus; D019590:Nucleocapsid Proteins; D014760:Viral Fusion Proteins; D014763:Viral Matrix Proteins