A recombinant measles virus unable to antagonize STAT1 function cannot control inflammation and is attenuated in rhesus monkeys.
Measles remains a leading cause of death worldwide among children because it suppresses immune function. The measles virus (MV) P gene encodes three proteins (P, V, and C) that interfere with innate immunity, controlling STAT1, STAT2, mda5, and perhaps other key regulators of immune function. We identified here three residues in the shared domain of the P and V proteins-tyrosine 110, valine 112, and histidine 115-that function to retain STAT1 in the cytoplasm and inhibit interferon transcription. This information was used to generate a recombinant measles virus unable to antagonize STAT1 function (STAT1-blind MV) differing only in these three residues from a wild-type strain of well-defined virulence. This virus was used to assess the relevance of P and V interactions with STAT1 for virulence in primates. When a group of six rhesus monkeys (Macaca mulatta) was inoculated intranasally with STAT1-blind MV, viremia was short-lived, and the skin rash and other clinical signs observed with wild-type MV were absent. The STAT1-blind virus less efficiently controlled the inflammatory response, as measured by enhanced transcription of interleukin-6 and tumor necrosis factor alpha in peripheral blood mononuclear cells from infected hosts. Importantly, neutralizing antibody titers and MV-specific T-cell responses were equivalent in hosts infected with either virus. These findings indicate that efficient MV interactions with STAT1 are required to sustain virulence in a natural host by controlling the inflammatory response against the virus. They also suggest that selectively STAT1-blind MV may have utility as vectors for targeted oncolysis and vaccination.
Devaux
Patricia
P
Department of Molecular Medicine, Mayo Clinic and Foundation, Guggenheim 18-01B, 200 First Street SW, Rochester, MN 55905, USA. devaux.patricia@mayo.edu
Hudacek
Andrew W
AW
Hodge
Gregory
G
Reyes-Del Valle
Jorge
J
McChesney
Michael B
MB
Cattaneo
Roberto
R
D000595:Amino Acid Sequence; D000818:Animals; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D008253:Macaca mulatta; D008457:Measles / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D008458:Measles Vaccine / Q000235:genetics / Q000276:immunology; D008459:Measles virus / Q000235:genetics / Q000472:pathogenicity*; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011995:Recombination, Genetic; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014709:Vero Cells; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014774:Virulence
D008458:Measles Vaccine; C055859:P protein, Sendai virus; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C069181:V protein, measles virus; D014764:Viral Proteins