20980517
not annotated - annotated - LINNAEUS only
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.
Ann file
T1 Species 14 27 measles virus
N1 Reference T1 Taxonomy:11234
T2 Species 113 127 rhesus monkeys
N2 Reference T2 Taxonomy:9544
T3 Species 240 253 measles virus
N3 Reference T3 Taxonomy:11234
T4 Species 255 257 MV
N4 Reference T4 Taxonomy:11234
T5 Species 685 698 measles virus
N5 Reference T5 Taxonomy:11234
T6 Species 748 750 MV
N6 Reference T6 Taxonomy:11234
T7 Species 968 982 rhesus monkeys
N7 Reference T7 Taxonomy:9544
T8 Species 984 998 Macaca mulatta
N8 Reference T8 Taxonomy:9544
T9 Species 1045 1047 MV
N9 Reference T9 Taxonomy:11234
T10 Species 1141 1143 MV
N10 Reference T10 Taxonomy:11234
T11 Species 1426 1428 MV
N11 Reference T11 Taxonomy:11234
T12 Species 1547 1549 MV
N12 Reference T12 Taxonomy:11234
T13 Species 1733 1735 MV
N13 Reference T13 Taxonomy:11234