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J. Virol. doi:10.1128/JVI.01798-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Cooperative effect of the attenuation determinants derived from poliovirus Sabin 1 strain is essential for attenuation of enterovirus 71 in the NOD/SCID mouse infection model

Department of Virology II and Division of Experimental Animals Research, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan

^* To whom correspondence should be addressed. Email: minetaro{at}nih.go.jp.

	Abstract

Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease, and is also associated with serious neurological disorders. An attenuated EV71 strain (EV71(S1-3')) has been established in the cynomolgus monkey infection model; this strain contains the attenuation determinants derived from type 1 poliovirus (PV) vaccine strain (Sabin 1) in the 5' non-translated region (NTR), 3D polymerase, and in the 3' NTR. In this study, we analyzed the effect of the attenuation determinants of PV1(Sabin) on EV71 infection in a NOD/SCID mouse infection model. We isolated a mouse-adapted EV71 strain (EV71(NOD/SCID)) that causes paralysis of the hindlimbs in 3- to 4-week-old NOD/SCID mice by adaptation of the virulent EV71(Nagoya) strain in the brain of NOD/SCID mice. A single mutation at nt 2876 that caused an amino acid change in a capsid protein VP1 (change of the amino acid residue 145 glycine to glutamic acid) was essential for the mouse-adapted phenotype in NOD/SCID mice. Next, we introduced attenuation determinants derived from PV1(Sabin) along with the mouse-adaptation mutation into the EV71(Nagoya) genome. In 4-week-old mice, the determinants in the 3D polymerase and 3'NTR, which are the major temperature-sensitive determinants, had a strong effect on attenuation. In contrast, the effect of individual determinants was weak in 3-week-old NOD/SCID mice, and all the determinants were required for substantial attenuation. These results suggest that a cooperative effect of the attenuation determinants of PV1(Sabin) is essential for attenuated neurovirulence of EV71.

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