J Gen Virol 86 (2005), 1391-1401; DOI 10.1099/vir.0.80784-0
© 2005 Society for General Microbiology
Temperature-sensitive mutants of enterovirus 71 show attenuation in cynomolgus monkeys
Minetaro Arita1,
Hiroyuki Shimizu1,
Noriyo Nagata2,
Yasushi Ami3,
Yuriko Suzaki3,
Tetsutaro Sata2,
Takuya Iwasaki4 and
Tatsuo Miyamura1
1 Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan
2 Department of Pathology, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan
3 Division of Experimental Animals Research, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan
4 Division of Clinical Investigation, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan
Correspondence
Minetaro Arita
minetaro{at}nih.go.jp
Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease and is sometimes associated with serious neurological disorders. In this study, an attempt was made to identify molecular determinants of EV71 attenuation of neurovirulence in a monkey infection model. An infectious cDNA clone of the virulent strain of EV71 prototype BrCr was constructed; temperature-sensitive (ts) mutations of an attenuated strain of EV71 or of poliovirus (PV) Sabin vaccine strains were then introduced into the infectious clone. In vitro and in vivo phenotypes of the parental and mutant viruses were analysed in cultured cells and in cynomolgus monkeys, respectively. Mutations in 3D polymerase (3Dpol) and in the 3' non-translated region (NTR), corresponding to ts determinants of Sabin 1, conferred distinct temperature sensitivity to EV71. An EV71 mutant [EV71(S1-3')] carrying mutations in the 5' NTR, 3Dpol and in the 3' NTR showed attenuated neurovirulence, resulting in limited spread of virus in the central nervous system of monkeys. These results indicate that EV71 and PV1 share common genetic determinants of neurovirulence in monkeys, despite the distinct properties in their original pathogenesis.
The GenBank/EMBL/DDBJ accession numbers for the complete genomic sequences of EV71(BrCr-TR) and EV71(BrCr-ts) are AB204852 and AB204853, respectively.
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Copyright © 2005 by the Society for General Microbiology.
