HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation.
HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation.
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DOI：
10.1371/journal.ppat.1006348
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发表时间：
2017-05
期刊：
影响因子：
6.7
通讯作者：
Sato K
中科院分区：
文献类型：
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作者：
Nakano Y;Misawa N;Juarez-Fernandez G;Moriwaki M;Nakaoka S;Funo T;Yamada E;Soper A;Yoshikawa R;Ebrahimi D;Tachiki Y;Iwami S;Harris RS;Koyanagi Y;Sato K
APOBEC 3（A3）家族蛋白是DNA胞嘧啶脱氨酶，被认为有助于HIV-1的限制和突变。先前的研究已经证明，A3 D、A3 F和A3 G酶在细胞培养物和人源化小鼠模型中引发稳健的抗HIV-1作用。人类A3 H是多态性的，并且可以分为三种表型：稳定型、中间型和不稳定型。然而，内源性A3 H在体内的抗病毒作用还有待研究。在这里，我们利用造血干细胞移植的人源化小鼠模型，并证明稳定的A3 H强烈影响体内HIV-1的适应性。相反，由中间体A3 H介导的选择压力是松弛的。有趣的是，病毒基因组RNA测序揭示了HIV-1在人源化小鼠中复制期间经常适应更好地抵消稳定的A3 H。分子系统发育分析和数学建模表明，稳定的A3 H可能是人与人之间病毒传播的关键因素。综上所述，这项研究提供了A3 H稳定变体对HIV-1施加选择性压力的证据。人APOBEC 3家族蛋白被认为是针对HIV-1的内在防御，而HIV-1 Vif抵消APOBEC 3介导的抗病毒作用。使用造血干细胞移植的人源化小鼠模型，我们证明了内源性APOBEC 3D，APOBEC 3F和APOBEC 3G在体内限制HIV-1复制中起关键作用。除了这三种APOBEC 3家族蛋白外，APOBEC 3 H的某些单倍型在细胞培养研究中具有控制HIV-1复制的能力。然而，APOBEC 3 H多态性在体内和人群中的抗病毒作用尚未得到解决。在这里，我们使用人源化小鼠模型来证明获得对抗病毒APOBEC 3 H的抗性是HIV-1复制所必需的。结合系统发育分析和数学建模，我们得出结论，APOBEC 3 H是感染者体内HIV-1复制的关键决定因素，我们认为它也可能是人与人之间HIV-1传播的一个因素。
APOBEC3 (A3) family proteins are DNA cytosine deaminases recognized for contributing to HIV-1 restriction and mutation. Prior studies have demonstrated that A3D, A3F, and A3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in humanized mouse models. Human A3H is polymorphic and can be categorized into three phenotypes: stable, intermediate, and unstable. However, the anti-viral effect of endogenous A3H in vivo has yet to be examined. Here we utilize a hematopoietic stem cell-transplanted humanized mouse model and demonstrate that stable A3H robustly affects HIV-1 fitness in vivo. In contrast, the selection pressure mediated by intermediate A3H is relaxed. Intriguingly, viral genomic RNA sequencing reveled that HIV-1 frequently adapts to better counteract stable A3H during replication in humanized mice. Molecular phylogenetic analyses and mathematical modeling suggest that stable A3H may be a critical factor in human-to-human viral transmission. Taken together, this study provides evidence that stable variants of A3H impose selective pressure on HIV-1. Human APOBEC3 family proteins are known as intrinsic defenses against HIV-1, whereas HIV-1 Vif counteracts APOBEC3-mediated anti-viral action. Using a hematopoietic stem cell-transplanted humanized mouse model, we demonstrated that endogenous APOBEC3D, APOBEC3F and APOBEC3G play pivotal roles in restricting HIV-1 replication in vivo. In addition to these three APOBEC3 family proteins, certain haplotypes of APOBEC3H have the ability to control HIV-1 replication in cell culture studies. However, the anti-viral effect of APOBEC3H polymorphism in vivo and in human population is yet to be addressed. Here we use a humanized mouse model to show that acquiring resistance to anti-viral APOBEC3H is necessary for HIV-1 replication. Together with phylogenetic analyses and mathematical modeling, we conclude that APOBEC3H is a critical determinant of HIV-1 replication within infected individuals and we propose that it may also be a factor in human-to-human HIV-1 transmission.