Persistence of viremia and production of neutralizing antibodies differentially regulated by polymorphic APOBEC3 and BAFF-R loci in Friend virus-infected mice
Persistence of viremia and production of neutralizing antibodies differentially regulated by polymorphic APOBEC3 and BAFF-R loci in Friend virus-infected mice
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弗兰德病毒感染小鼠中病毒血症的持续存在以及中和抗体的产生受多态性 APOBEC3 和 BAFF-R 基因座的差异调节
DOI：
10.1128/jvi.02516-09
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发表时间：
2010
期刊：
影响因子：
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通讯作者：
M. Miyazawa
中科院分区：
文献类型：
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作者：
Tsuji-Kawahara;S.;T. Chikaishi;E. Takeda;M. Kato;S. Kinoshita;E. Kajiwara;S. Takamura;M. Miyazawa
一些宿主基因通过调节对病毒抗原的免疫应答来控制逆转录病毒的复制和发病机制。Rfv 3基因影响Friend小鼠逆转录病毒复合体（FV）感染小鼠的病毒血症持续性和病毒中和抗体的产生。该基因座已被定位在小鼠15号染色体的一个狭窄区段内，该区段含有APOBEC 3和BAFF-R基因座，这两个基因座在不同品系的小鼠中均显示出功能多态性。在FV抗性C57 BL/6（B6）小鼠中表达的APOBEC 3等位基因的外显子5缺失产物直接限制病毒复制，并且缺乏B6衍生的APOBEC 3的小鼠表现出夸大的病理学和减少的中和抗体产生。然而，APOBEC 3位点多态性影响中和抗体产生的机制仍不清楚。在这里，我们发现APOBEC 3基因型并不直接影响B细胞库，缺乏B6衍生的APOBEC 3的小鼠在存在致敏的T辅助细胞的情况下仍然产生FV中和抗体。相反，由于缺乏B6-衍生的APOBEC 3或缺乏野生型BAFF-R而导致的FV感染早期较高的病毒载量导致中和抗体的产生较慢。事实上，APOBEC 3或BAFF-R缺陷小鼠感染后不久，B细胞就被过度激活。与缺乏B6衍生的APOBEC 3的小鼠在FV感染后4周清除病毒血症相反，缺乏功能性BAFF-R等位基因的小鼠表现出持续的病毒血症，表明BAFF-R基因座的多态性可能更好地解释Rfv 3定义的持续病毒血症表型。
Several host genes control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. TheRfv3gene influences the persistence of viremia and production of virus-neutralizing antibodies in mice infected with Friend mouse retrovirus complex (FV). This locus has been mapped within a narrow segment of mouse chromosome 15 harboring theAPOBEC3andBAFF-Rloci, both of which show functional polymorphisms among different strains of mice. The exon 5-lacking product of theAPOBEC3allele expressed in FV-resistant C57BL/6 (B6) mice directly restricts viral replication, and mice lacking the B6-derivedAPOBEC3exhibit exaggerated pathology and reduced production of neutralizing antibodies. However, the mechanisms by which the polymorphisms at theAPOBEC3locus affect the production of neutralizing antibodies remain unclear. Here we show that theAPOBEC3genotypes do not directly affect the B-cell repertoire, and mice lacking B6-derivedAPOBEC3still produce FV-neutralizing antibodies in the presence of primed T helper cells. Instead, higher viral loads at a very early stage of FV infection caused by either a lack of the B6-derivedAPOBEC3or a lack of the wild-typeBAFF-Rresulted in slower production of neutralizing antibodies. Indeed, B cells were hyperactivated soon after infection in theAPOBEC3- orBAFF-R-deficient mice. In contrast to mice deficient in the B6-derivedAPOBEC3, which cleared viremia by 4 weeks after FV infection, mice lacking the functionalBAFF-Rallele exhibited sustained viremia, indicating that the polymorphisms at theBAFF-Rlocus may better explain theRfv3-defining phenotype of persistent viremia.