MAPPING OF MUTATIONS CONTRIBUTING TO THE TEMPERATURE SENSITIVITY OF THE SABIN-1 VACCINE STRAIN OF POLIOVIRUS
MAPPING OF MUTATIONS CONTRIBUTING TO THE TEMPERATURE SENSITIVITY OF THE SABIN-1 VACCINE STRAIN OF POLIOVIRUS
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DOI：
10.1128/jvi.69.9.5278-5286.1995
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发表时间：
1995-09-01
影响因子：
5.4
通讯作者：
DELPEYROUX, F
中科院分区：
文献类型：
--
作者：
GEORGESCU, MM;TARDYPANIT, M;DELPEYROUX, F
脊髓灰质炎病毒Sabin 1型疫苗株的温度敏感和减毒表型是由毒力强的马奥尼病毒亲本中发生的许多点突变引起的。其中一个突变位于3D聚合酶（3D(Pol)）密码子（U-6203—b> C, Tyr 73—>His）上，并参与普通小鼠的衰减（M. Tardy-Panit， B. Blondel, a . Martin， F. Tekaia， F. Horaud， F. Delpeyroux， J. Virol. 67:4630-4638, 1993）。该突变似乎还与基因组3‘端部分（包括3D（Pol）编码区和3’非编码区）的10个突变中的至少1个突变有关。为了绘制其他突变，我们通过诱变和重组Mahoney和Sabin 1 cdna构建了脊髓灰质炎病毒突变体。这些脊髓灰质炎病毒突变体的特征表明，3D（Pol）密码子（C-7071—>U, Thr-362—>Ile）的第二个突变有助于温度敏感性。基因组3'非编码区（A-7441- >G）的突变，单独或与另一个突变（U-7410- >C）相关联，似乎也与这种表型有关。与Sabin 1基因组3′端部分相关的温度敏感效应来自至少三个遗传决定因素的累积和/或协同效应，即3D（Pol）的His-73和Ile-362密码子和核苷酸G-7441。从疫苗相关麻痹性脊髓灰质炎患者中分离的菌株序列分析显示，这些遗传决定因素在体内被选择对抗，尽管Ile-362密码子似乎比His-73密码子或G-7441更稳定。这些遗传决定因素可能有助于Sabin 1在疫苗接种者中的安全性。
The temperature-sensitive and attenuated phenotypes of the Sabin type 1 vaccine strain of poliovirus result from numerous point mutations which occurred in the virulent Mahoney virus parent. One of these mutations is located in a 3D polymerase (3D(Pol)) codon (U-6203-->C, Tyr 73-->His) and is involved in attenuation in common mice (M. Tardy-Panit, B. Blondel, A. Martin, F. Tekaia, F. Horaud, and F. Delpeyroux, J. Virol. 67:4630-4638, 1993). This mutation also appears to contribute to temperature sensitivity in association with at least 1 other of the 10 mutations of the 3'-terminal part of the genome including the 3D(Pol) coding and 3' noncoding regions. To map the other mutation(s), we constructed poliovirus mutants by mutagenesis and recombination of Mahoney and Sabin 1 cDNAs. Characterization of these poliovirus mutants showed that a second mutation in a 3D(Pol) codon (C-7071-->U, Thr-362-->Ile) contributes to temperature sensitivity. A mutation in the 3' noncoding region of the genome (A-7441-->G), alone or linked to another mutation (U-7410-->C), also appeared to be involved in this phenotype. The temperature-sensitive effect associated with the 3'-terminal part of the Sabin 1 genome results from the cumulative and/or synergistic effects of at least three genetic determinants, i.e., the His-73 and Ile-362 codons of 3D(Pol) and nucleotide G-7441. Sequence analysis of strains isolated from patients with vaccine-associated paralytic poliomyelitis showed that these genetic determinants are selected against in vivo, although the Ile-362 codon appeared to be more stable than either the His-73 codon or G-7441. These genetic determinants may contribute to the safety of Sabin 1 in vaccinees.