臨床検査50巻13号

2006年12月発行

シリーズ最新医学講座・Ⅱ 耐性菌の基礎と臨床・11 ウイルスの薬剤耐性・2

インフルエンザウイルス(基礎編)

著者： 信澤枝里¹

所属機関： ¹名古屋市立大学大学院医学研究科感染微生物

ページ範囲：P.1709 - P.1715

はじめに

　インフルエンザウイルスは，膜を被った膜ウイルスの一種(図1)で，変異が著しいことが知られている．この変異の原因は，ウイルスの複製にかかわる酵素(RNAポリメラーゼ)(図1参照)が「賢くない」ことにある．つまり，遺伝子の情報が子ウイルスに正確に伝わらないのである．そのため，感染細胞から出てくる子ウイルスのなかには，親ウイルスとは異なる遺伝情報(変異)を持つウイルスがいる．その変異が抗ウイルス薬との結合を妨げる場合，そのウイルスは薬剤耐性になる．薬剤耐性ウイルスとは，“薬剤を使用したために変異が生じたウイルス”ではない．薬剤使用の有無にかかわらず，変異ウイルスは一定の割合で生じている．そのウイルスを薬剤によって選択した結果，検出されたのが，薬剤耐性ウイルスである．

参考文献

　１) Davies WL, Grunert RR, Haff RF, et al：Antiviral activity of 1-adamantanamine (amantadine). Science　144：862-863, 1964

　２) von Itzstein M, Wu W-Y, Kok GB, et al：Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature　363：418-423, 1993

　３) Hay AJ：The action of adamantanamines against influenza A viruses：inhibition of the M2 ion channel protein. Semmin Virol　3：21-30, 1992

　４) Helenius A：Unpacking the incoming influenza virus. Cell　69：577-578, 1992

　５) Holsinger LJ, Lamb RA：Influenza virus M2 integral membrane protein is a homotetramer stabilized by formation of disulfide bonds. Virology　183：32-43, 1991

　６) Sugrue RJ, Hay AJ：Structural characteristics of the M2 protein of the influenza A viruses：Evidence that it forms a tetrameric channel. Virolgy　180：617-624, 1991.

　７) Sakaguchi T, Tu Q, Pinto LH et al：The active oligomeric state of the minimalistic influenza virus M2 ion channel is a tetramer. Proc Natl Acad Sci USA　94：5000-5005, 1997

　８) Sansom MS, Ker ID, Smith GR, et al：The influenza A virus M2 channel：A molecular modeling and simulation study. Virology　233：163-173, 1997

　９) Saito R, Sakai T, Sato I, et al：Frequency of amantadine-resistant influenza A viruses during two seasons featuring cocirculation of H1N1 and H3N2. J Clin Microbiol　41：2164-2165, 2003

　10) Astrahan P, Kass I, Cooper MA, et al：A novel method of resistance for influenza against a channel-blocking antiviral drug. Proteins　55：251-257, 2004

　11) Bright RA, Medina M-J, Xu X, et al：Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005：a cause for concern. Lancet　366：1175-1181, 2005

　12) Bright RA, Shay DK, Shu B, et al：Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. JAMA　295：891-894, 2006

　13) Harper SA, Fukuda K, Uyeld TM, et al：Prevention and control of influenza. MMWR Recomm Rep　54：1-40, 2005

　14) Shiraishi K, Mitamura K, Sakai-Tagawa Y：High frequency of resistant viruses harboring different mutations in amantadine-treated children with influenza. J Infect Dis　188：57-61, 2003

　15) Saito R, Oshitani H, Masuda H, et al：Detection of amantadine-resistant influenza A virus strains in nursing homes by PCR-restriction fragment length polymorphism analysis with nasopharyngeal swabs. J Clin Microbiol　40：84-88, 2002

　16) Kim CU, Lew W, Williams MA, et al：Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site：design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc　119：681-690, 1997

　17) Gubareva LV, Webster RG, Hayden FG：Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants. Antimicro Agents Chemother　45：3403-3408, 2001

　18) Herlocher ML, Carr J, Ives J, et al：Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets. Antiviral Res　54：99-111, 2002

　19) Herlocher ML, Truscon R, Elias S, et al：Influenza viruses resistant to the antiviral drug oseltamivir：transmission studies in ferrets. J Infect Dis　190：1627-1630, 2004

　20) Yen HL, Herlocher ML, Hoffmann E, et al：Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. J Virol　49：4075-4084, 2005

　21) Blick TJ, Sahasrabudhe A, McDonald M, et al：The interaction of neuraminidase and hemagglutinin mutations in influenza virus in resistance to 4-guanidino-Neu5Ac2en. Virology　246：95-103, 1998

　22) Gubareva LV, Bethell R, Hart GJ, et al：Characterization of mutants of influenza A virus selected with neuraminidase inhibitor 4-guanidino-NeuAc2en. J Virol　70：1818-1827, 1996

　23) Gubareva LV, Matrosovich MN, Brenner MK, et al：Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis　178：1257-1262, 1998

　24) Tai CY, Escarrpe PA, Sidwell RW, et al：Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071. Antimicrob Agents Chemother　42：3234-3241, 1998

　25) Nobusawa E, Nakajima K, Kozuka S, et al：Change in receptor-binding specificity of recent human influenza A viruses (H3N2) affects recognition of the receptor on MDCK cells. In：International Congress Series. Options for the control of influenza V. (Kawaoka Y, ed), Elsevier BV, Amsterdam, pp472-475, 2004

　26) Gubareva LV, Matrosovich MN, Brenner MK, et al：Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis　178：1257-1262, 1998

　27) Jackson HC, Roberts N, Wang ZM, et al：Management of influenza. Use of new antivirals and resistance in perspective. Clin Drug Invest　29：447-454, 2000

　28) Gubareva LV, Katser L, Matrosovich MN, et al：Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir. J Infect Dis　183：523-531, 2001

　29) Roberts NA：Treatment of influenza with neuraminidase inhibitors：virological implications. Philos Trans R Soc Lond B Biol Sci　356：1895-1897, 2001

　30) Kiso M, Mitamura K, Sakai-Tagawa Y, et al：Resistant influenza A viruses in children treated with oseltamivir：descriptive study. Lancet　364：759-765, 2004

　31) Mishin VP, Hayden FG, Gubareva LV：Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors. Antimicro Agents Chemother　49：4515-4520, 2005

　32) Lamb RA, Krug RM：Orthomyxoviridae：The viruses and their replication. In：Fields Virology (Fields BN, Knipe DM, Howley PM, eds), Lippincott-Raven, Philadelphia, pp1353-1396, 1996

　33) Lamb RA, Holsinger LJ, Pinto LH：The influenza A virus M2 ion channel protein and its role in the influenza virus life cycle. In Recepor-mediated virus entry into cells (Wimmer E, eds), Cold Springg Harbor Press, New York, pp303-321, 1994