Department of Immunology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
J Virol. 2010 Jun;84(12):6082-95. doi: 10.1128/JVI.02516-09. Epub 2010 Apr 7.
Several host genes control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. The Rfv3 gene 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 the APOBEC3 and BAFF-R loci, both of which show functional polymorphisms among different strains of mice. The exon 5-lacking product of the APOBEC3 allele expressed in FV-resistant C57BL/6 (B6) mice directly restricts viral replication, and mice lacking the B6-derived APOBEC3 exhibit exaggerated pathology and reduced production of neutralizing antibodies. However, the mechanisms by which the polymorphisms at the APOBEC3 locus affect the production of neutralizing antibodies remain unclear. Here we show that the APOBEC3 genotypes do not directly affect the B-cell repertoire, and mice lacking B6-derived APOBEC3 still 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-derived APOBEC3 or a lack of the wild-type BAFF-R resulted in slower production of neutralizing antibodies. Indeed, B cells were hyperactivated soon after infection in the APOBEC3- or BAFF-R-deficient mice. In contrast to mice deficient in the B6-derived APOBEC3, which cleared viremia by 4 weeks after FV infection, mice lacking the functional BAFF-R allele exhibited sustained viremia, indicating that the polymorphisms at the BAFF-R locus may better explain the Rfv3-defining phenotype of persistent viremia.
几种宿主基因通过调节对病毒抗原的免疫反应来控制逆转录病毒的复制和发病机制。Rfv3 基因影响感染 Friend 鼠逆转录病毒复合物（FV）的小鼠中病毒血症的持续时间和病毒中和抗体的产生。该基因座已被定位在含有 APOBEC3 和 BAFF-R 基因座的小鼠 15 号染色体的一个狭窄片段内，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 C57BL/6（B6）小鼠中表达的 APOBEC3 等位基因缺失外显子 5 的产物直接限制病毒复制，而缺乏 B6 衍生的 APOBEC3 的小鼠表现出更严重的病理和中和抗体产生减少。然而，APOBEC3 基因座的多态性影响中和抗体产生的机制仍不清楚。我们在这里表明，APOBEC3 基因型不会直接影响 B 细胞库，并且在存在已被激活的辅助性 T 细胞的情况下，缺乏 B6 衍生的 APOBEC3 的小鼠仍然可以产生 FV 中和抗体。相反，由于缺乏 B6 衍生的 APOBEC3 或缺乏野生型 BAFF-R，FV 感染的非常早期阶段的病毒载量更高，导致中和抗体的产生较慢。事实上，在 APOBEC3 或 BAFF-R 缺陷型小鼠中，感染后不久 B 细胞就被过度激活。与在 FV 感染后 4 周清除病毒血症的缺乏 B6 衍生的 APOBEC3 的小鼠相比，缺乏功能性 BAFF-R 等位基因的小鼠表现出持续的病毒血症，这表明 BAFF-R 基因座的多态性可能更好地解释 Rfv3 定义的持续性病毒血症表型。
