An Alu Element Insertion in Intron 1 Results in Aberrant Alternative Splicing of APOBEC3G Pre-mRNA in Northern Pig-Tailed Macaques (Macaca leonina) That May Reduce APOBEC3G-Mediated Hypermutation Pressure on HIV-1
An Alu Element Insertion in Intron 1 Results in Aberrant Alternative Splicing of APOBEC3G Pre-mRNA in Northern Pig-Tailed Macaques (Macaca leonina) That May Reduce APOBEC3G-Mediated Hypermutation Pressure on HIV-1
复制标题
内含子 1 中的 Alu 元素插入导致北方猪尾猕猴 (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
DOI：
10.1128/jvi.01722-19
复制
发表时间：
2020-02-01
影响因子：
5.4
通讯作者：
Zheng，Yong-Tang
中科院分区：
文献类型：
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作者：
Zhang，Xiao-Liang;Luo，Meng-Ting;Zheng，Yong-Tang
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，靶向APOBEC3G用于艾滋病治疗的研究受到越来越多的关注。为了适当地利用猕猴动物模型来研究APOBEC3相关问题，澄清人类和猕猴APOBEC3之间的区别是很重要的。在本研究中，我们在猕猴中发现了一种新的、保守的APOBEC3G前mRNA选择性剪接模式，这种剪接模式不同于人类，它可能降低了APOBEC3G介导的北部猪尾猕猴(NPM)对HIV-1的高突变压力。我们的工作为在艾滋病研究中正确应用APOBEC3相关问题的猕猴动物模型和更好地理解APOBEC3蛋白的生物学功能提供了重要信息。摘要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。由APOBEC3引起的病毒超突变与病毒进化、病毒传播和疾病进展有关。近年来，靶向APOBEC3G用于艾滋病治疗的研究越来越受到重视。因此，对于APOBEC3相关问题的研究，需要一个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一个相对理想的体内系统。为了适当地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APOBEC3G介导的/APOBEC3介导的HIV-1高突变足迹在北方猪尾猕猴的外周血单个核细胞(PBMC)中的比例远远低于人类的PBMC。接下来，我们在猕猴中发现了一种新的、保守的APOBEC3G前mRNA选择性剪接模式，它不同于人类，是由于Alu元件插入到猕猴APOBEC3G基因内含子1中。这种产生异常APOBEC3G mRNA异构体的选择性剪接模式可能显著稀释北方猪尾猕猴的全长APOBEC3G，并降低APOBEC3G介导的对HIV-1的高突变压力，这得到了消除导致两种宿主之间这种超突变差异的其他可能性的支持。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，靶向APOBEC3G用于艾滋病治疗的研究受到越来越多的关注。为了适当地利用猕猴动物模型来研究APOBEC3相关问题，澄清人类和猕猴APOBEC3之间的区别是很重要的。在本研究中，我们在猕猴中发现了一种新的、保守的APOBEC3G前mRNA选择性剪接模式，这种剪接模式不同于人类，它可能降低了APOBEC3G介导的北部猪尾猕猴(NPM)对HIV-1的高突变压力。我们的工作为在艾滋病研究中正确应用APOBEC3相关问题的猕猴动物模型和更好地理解APOBEC3蛋白的生物学功能提供了重要信息。
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. ABSTRACT 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.