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Journal of Virology, September 2007, p. 9386-9395, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.02856-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

An Attenuated Strain of Enterovirus 71 Belonging to Genotype A Showed a Broad Spectrum of Antigenicity with Attenuated Neurovirulence in Cynomolgus Monkeys{triangledown}

Minetaro Arita,1* Noriyo Nagata,2 Naoko Iwata,2 Yasushi Ami,3 Yuriko Suzaki,3 Katsumi Mizuta,4 Takuya Iwasaki,5 Tetsutaro Sata,2 Takaji Wakita,1 and Hiroyuki Shimizu1

Department of Virology II,1 Department of Pathology,2 Division of Experimental Animals Research, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan,3 Department of Microbiology, Yamagata Prefectural Institute of Public Health, Tokamachi 1-6-6, Yamagata, 990-0031 Japan,4 Division of Clinical Investigation, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan5

Received 25 December 2006/ Accepted 5 June 2007

Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and is also sometimes associated with serious neurological disorders. In this study, we characterized the antigenicity and tissue specificity of an attenuated strain of EV71 [EV71(S1-3')], which belongs to genotype A, in a monkey infection model. Three cynomolgus monkeys were inoculated with EV71(S1-3'), followed by lethal challenge with the parental virulent strain EV71(BrCr-TR) via an intravenous route on day 45 postinoculation of EV71(S1-3'). Monkeys inoculated with EV71(S1-3') showed a mild neurological symptom (tremor) but survived lethal challenge by virulent EV71(BrCr-TR) without exacerbation of the symptom. The immunized monkey sera showed a broad spectrum of neutralizing activity against different genotypes of EV71, including genotypes A, B1, B4, C2, and C4. For the strains examined, the sera showed the highest neutralization activity against the homotype (genotype A) and the lowest neutralization activity against genotype C2. The order of decreasing neutralization activity of sera was as follows: A > B1 > C4 > B4 > C2. To examine the tissue specificity of EV71(S1-3'), two monkeys were intravenously inoculated with EV71(S1-3'), followed by examination of virus distribution in the central nervous system (CNS) and extraneural tissues. In the CNS, EV71(S1-3') was isolated only from the spinal cord. These results indicate that EV71(S1-3') acts as an effective antigen, although this attenuated strain was still neurotropic when inoculated via the intravenous route.

* Corresponding author. Mailing address: Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan. Phone: 81-42-561-0771. Fax: 81-42-561-4729. E-mail: minetaro{at}nih.go.jp

{triangledown} Published ahead of print on 13 June 2007.

Journal of Virology, September 2007, p. 9386-9395, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.02856-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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