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Viral mutation accelerated by nitric oxide production during infection in vivo

TAKAAKI AKAIKE¹, SHIGEMOTO FUJII, ATSUSHI KATO^*, JUN YOSHITAKE, YOICHI MIYAMOTO, TOMOHIRO SAWA, SHINICHIRO OKAMOTO, MORITAKA SUGA, MAKOTO ASAKAWA, YOSHIYUKI NAGAI^* and HIROSHI MAEDA

Departments of Microbiology and Medicine I, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan;
^* Department of Viral Infection, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan; and
DNAVEC Research Institute, Tsukuba, Japan

¹Correspondence: Department of Microbiology, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan. E-mail: takakaik{at}gpo.kumamoto-u.ac.jp

Nitric oxide (NO), superoxide (O₂^-), and their reaction product peroxynitrite (ONOO^-) are generated in excess during a host’s response against viral infection, and contribute to viral pathogenesis by promoting oxidative stress and tissue injury. Here we demonstrate that NO and peroxynitrite greatly accelerates the mutation of Sendai virus (SeV), a nonsegmented negative-strand RNA virus, by using green fluorescent protein (GFP) inserted into and expressed by a recombinant SeV (GFP-SeV) as an indicator for mutation. GFP-SeV mutation frequencies were much higher in the wild-type mice than in those lacking inducible NO synthase, suggesting that mutation of the virus in vivo is NO dependent. High levels of NO and NO-mediated oxidative stress were induced by GFP-SeV infection in the lung of the wild-type mice, but not in the iNOS-deficient mice, as evidenced by electron spin resonance spectroscopy and immunohistochemical analysis for nitrotyrosine formation as well as histopathological examination. Furthermore, peroxynitrite, an NO-derived reactive nitrogen intermediate, enhanced viral mutation in vitro. These results indicate that the oxidative stress induced by NO produced during the natural course of viral infection increases mutation, expands the quasispecies spectrum, and facilitates evolution of RNA viruses.—Akaike, T., Fujii, S., Kato, A., Yoshitake, J., Miyamoto, Y., Sawa, T., Okamoto, S., Suga, M., Asakawa, M., Nagai, Y., Maeda, H. Viral mutation accelerated by nitric oxide production during infection in vivo.

Key Words: NO • peroxynitrite • oxidative stress

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