APOBEC3 family members, particularly APOBEC3F and APOBEC3G, inhibit the replication and spread of various retroviruses by inducing hypermutation in newly synthesized viral DNA. Viral hypermutation by APOBEC3 is associated with viral evolution, viral transmission, and disease progression. In recent years, increasing attention has been paid to targeting APOBEC3G for AIDS therapy. Thus, a controllable model system using species such as macaques, which provide a relatively ideal in vivo system, is needed for the study of APOBEC3-related issues. To appropriately utilize this animal model for biomedical research, important differences between human and macaque APOBEC3s must be considered. In this study, we found that the ratio of APOBEC3G-mediated/APOBEC3-mediated HIV-1 hypermutation footprints was much lower in peripheral blood mononuclear cells (PBMCs) from northern pig-tailed macaques than in PBMCs from humans. Next, we identified a novel and conserved APOBEC3G pre-mRNA alternative splicing pattern in macaques, which differed from that in humans and resulted from an Alu element insertion into macaque APOBEC3G gene intron 1. This alternative splicing pattern generating an aberrant APOBEC3G mRNA isoform may significantly dilute full-length APOBEC3G and reduce APOBEC3G-mediated hypermutation pressure on HIV-1 in northern pig-tailed macaques, which was supported by the elimination of other possibilities accounting for this hypermutation difference between the two hosts.IMPORTANCE APOBEC3 family members, particularly APOBEC3F and APOBEC3G, are important cellular antiviral factors. Recently, more attention has been paid to targeting APOBEC3G for AIDS therapy. To appropriately utilize macaque animal models for the study of APOBEC3-related issues, it is important that the differences between human and macaque APOBEC3s are clarified. In this study, we identified a novel and conserved APOBEC3G pre-mRNA alternative splicing pattern in macaques, which differed from that in humans and which may reduce the APOBEC3G-mediated hypermutation pressure on HIV-1 in northern pig-tailed macaques (NPMs). Our work provides important information for the proper application of macaque animal models for APOBEC3-related issues in AIDS research and a better understanding of the biological functions of APOBEC3 proteins.

中文翻译：

---

在内含子 1 中插入 Alu 元素会导致北方猪尾猕猴 (Macaca leonina) 中 APOBEC3G 前体 mRNA 的异常选择性剪接，这可能会减少 APOBEC3G 介导的 HIV-1 超突变压力。


APOBEC3家族成员，特别是APOBEC3F和APOBEC3G，通过诱导新合成的病毒DNA的超突变来抑制各种逆转录病毒的复制和传播。 APOBEC3 引起的病毒超突变与病毒进化、病毒传播和疾病进展相关。近年来，针对 APOBEC3G 的艾滋病治疗越来越受到关注。因此，需要一种利用猕猴等物种的可控模型系统，为APOBEC3相关问题的研究提供相对理想的体内系统。为了正确利用这种动物模型进行生物医学研究，必须考虑人类和猕猴 APOBEC3 之间的重要差异。在这项研究中，我们发现北方猪尾猕猴外周血单核细胞（PBMC）中 APOBEC3G 介导/APOBEC3 介导的 HIV-1 超突变足迹的比率远低于人类 PBMC。接下来，我们在猕猴中发现了一种新颖且保守的 APOBEC3G mRNA 前体选择性剪接模式，该模式与人类不同，是由 Alu 元件插入猕猴 APOBEC3G 基因内含子 1 引起的。这种产生异常 APOBEC3G mRNA 亚型的选择性剪接模式可能会显着影响稀释全长 APOBEC3G 并降低北方猪尾猕猴中 APOBEC3G 介导的 HIV-1 超突变压力，这通过消除解释两个宿主之间这种超突变差异的其他可能性得到支持。 重要性 APOBEC3 家族成员，特别是 APOBEC3F 和APOBEC3G，是重要的细胞抗病毒因子。近年来，针对APOBEC3G的艾滋病治疗受到越来越多的关注。 为了正确利用猕猴动物模型来研究 APOBEC3 相关问题，澄清人类和猕猴 APOBEC3 之间的差异非常重要。在这项研究中，我们在猕猴中发现了一种新颖且保守的 APOBEC3G mRNA 前体选择性剪接模式，该模式与人类不同，可能会降低北方猪尾猕猴 (NPM) 中 APOBEC3G 介导的 HIV-1 超突变压力。我们的工作为在艾滋病研究中正确应用猕猴动物模型解决 APOBEC3 相关问题以及更好地了解 APOBEC3 蛋白的生物学功能提供了重要信息。