Yoshikawa Rokusuke, Takeuchi Junko S, Yamada Eri, Nakano Yusuke, Misawa Naoko, Kimura Yuichi, Ren Fengrong, Miyazawa Takayuki, Koyanagi Yoshio, Sato Kei
Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
J Virol. 2017 May 12;91(11). doi: 10.1128/JVI.00250-17. Print 2017 Jun 1.
The interplay between viral and host proteins has been well studied to elucidate virus-host interactions and their relevance to virulence. Mammalian genes encode apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) proteins, which act as intrinsic restriction factors against lentiviruses. To overcome APOBEC3-mediated antiviral actions, lentiviruses have evolutionarily acquired an accessory protein, viral infectivity factor (Vif), and Vif degrades host APOBEC3 proteins via a ubiquitin/proteasome-dependent pathway. Although the Vif-APOBEC3 interaction and its evolutionary significance, particularly those of primate lentiviruses (including HIV) and primates (including humans), have been well investigated, those of nonprimate lentiviruses and nonprimates are poorly understood. Moreover, the factors that determine lentiviral pathogenicity remain unclear. Here, we focus on feline immunodeficiency virus (FIV), a pathogenic lentivirus in domestic cats, and the interaction between FIV Vif and feline APOBEC3 in terms of viral virulence and evolution. We reveal the significantly reduced diversity of FIV subtype B compared to that of other subtypes, which may associate with the low pathogenicity of this subtype. We also demonstrate that FIV subtype B Vif is less active with regard to feline APOBEC3 degradation. More intriguingly, we further reveal that FIV protease cleaves feline APOBEC3 in released virions. Taken together, our findings provide evidence that a lentivirus encodes two types of anti-APOBEC3 factors, Vif and viral protease. During the history of mammalian evolution, mammals coevolved with retroviruses, including lentiviruses. All pathogenic lentiviruses, excluding equine infectious anemia virus, have acquired the gene via evolution to combat APOBEC3 proteins, which are intrinsic restriction factors against exogenous lentiviruses. Here we demonstrate that FIV, a pathogenic lentivirus in domestic cats, antagonizes feline APOBEC3 proteins by both Vif and a viral protease. Furthermore, the Vif proteins of an FIV subtype (subtype B) have attenuated their anti-APOBEC3 activity through evolution. Our findings can be a clue to elucidate the complicated evolutionary processes by which lentiviruses adapt to mammals.
病毒蛋白与宿主蛋白之间的相互作用已得到充分研究，以阐明病毒 - 宿主相互作用及其与毒力的相关性。哺乳动物基因编码载脂蛋白B信使核糖核酸编辑酶催化多肽样3（APOBEC3）蛋白，其作为针对慢病毒的内在限制因子。为了克服APOBEC3介导的抗病毒作用，慢病毒在进化过程中获得了一种辅助蛋白，即病毒感染性因子（Vif），并且Vif通过泛素/蛋白酶体依赖性途径降解宿主APOBEC3蛋白。尽管Vif - APOBEC3相互作用及其进化意义，特别是灵长类慢病毒（包括HIV）和灵长类动物（包括人类）的相互作用已得到充分研究，但非灵长类慢病毒和非灵长类动物的相互作用却知之甚少。此外，决定慢病毒致病性的因素仍不清楚。在这里，我们聚焦于猫免疫缺陷病毒（FIV），一种家猫中的致病性慢病毒，以及FIV Vif与猫APOBEC3在病毒毒力和进化方面的相互作用。我们发现与其他亚型相比，FIV B亚型的多样性显著降低，这可能与该亚型的低致病性有关。我们还证明FIV B亚型Vif在降解猫APOBEC3方面活性较低。更有趣的是，我们进一步发现FIV蛋白酶在释放的病毒颗粒中切割猫APOBEC3。综上所述，我们的研究结果提供了证据，表明慢病毒编码两种类型的抗APOBEC3因子，即Vif和病毒蛋白酶。在哺乳动物进化史上，哺乳动物与包括慢病毒在内的逆转录病毒共同进化。除马传染性贫血病毒外，所有致病性慢病毒都通过进化获得了 基因以对抗APOBEC3蛋白，APOBEC3蛋白是针对外源慢病毒的内在限制因子。在这里，我们证明FIV，一种家猫中的致病性慢病毒，通过Vif和病毒蛋白酶拮抗猫APOBEC3蛋白。此外，FIV一个亚型（B亚型）的Vif蛋白通过进化减弱了其抗APOBEC3活性。我们的研究结果可以为阐明慢病毒适应哺乳动物的复杂进化过程提供线索。
