Equine Infectious Anemia Virus Resists the Antiretroviral Activity of Equine APOBEC3 Proteins through a Packaging-Independent Mechanism
Equine Infectious Anemia Virus Resists the Antiretroviral Activity of Equine APOBEC3 Proteins through a Packaging-Independent Mechanism
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DOI：
10.1128/jvi.01537-08
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发表时间：
2008-12-01
影响因子：
5.4
通讯作者：
Cullen, Bryan R.
中科院分区：
文献类型：
--
作者：
Bogerd, Hal P.;Tallmadge, Rebecca L.;Cullen, Bryan R.
马传染性贫血病毒（EIAV）是慢病毒中唯一不编码vif基因产物的病毒。其他慢病毒，包括人类免疫缺陷病毒1型（HIV-1），使用Vif来中和APOBEC 3（A3）家族的内在免疫因子，否则会抑制病毒感染性。这表明在体内被EIAV感染的马细胞不表达活性A3蛋白，或者EIAV已经开发了一种新的机制来避免马A3（eA 3）的抑制。在这里，我们证明，马编码六个不同的A3蛋白，其中四个包含一个拷贝的胞苷脱氨酶（CDA）的共识活性位点，其中两个包含两个CDA基序。这代表了以前只在灵长类动物中看到的复杂程度。马单CDA A3蛋白的系统发育分析揭示了两个与人A3 A（hA 3A）相关的蛋白，一个与hA 3C相关，一个与hA 3 H相关。两种马的双CDA蛋白类似于hA 3F，并被命名为eA 3F 1和eA 3F 2。对eA 3F 1和eA 3F 2体内表达的分析表明，编码这些蛋白质的mRNA广泛表达，包括在作为天然EIAV靶标的细胞中。eA 3F 1和eA 3F 2都能抑制反转录转座子的移动性，而eA 3F 1是一种Vif缺陷型HIV-1突变体的有效抑制剂，并诱导HIV-1逆转录物的广泛编辑。然而，eA 3F 1和eA 3F 2都是EIAV的弱抑制剂。令人惊讶的是，eA 3F 1和eA 3F 2被包装到EIAV和HIV-1病毒粒子中与hA 3G一样有效，尽管只有后者抑制EIAV的感染性。此外，所有三种蛋白质结合HIV-1和EIAV核衣壳蛋白特异性在体外。因此，似乎EIAV已经进化出一种新的机制，在病毒体掺入后的一个步骤中特异性中和同源eA 3F 1和eA 3F 2蛋白的生物活性。
Equine infectious anemia virus (EIAV), uniquely among lentiviruses, does not encode a vif gene product. Other lentiviruses, including human immunodeficiency virus type 1 (HIV-1), use Vif to neutralize members of the APOBEC3 (A3) family of intrinsic immunity factors that would otherwise inhibit viral infectivity. This suggests either that equine cells infected by EIAV in vivo do not express active A3 proteins or that EIAV has developed a novel mechanism to avoid inhibition by equine A3 (eA3). Here, we demonstrate that horses encode six distinct A3 proteins, four of which contain a single copy of the cytidine deaminase (CDA) consensus active site and two of which contain two CDA motifs. This represents a level of complexity previously seen only in primates. Phylogenetic analysis of equine single-CDA A3 proteins revealed two proteins related to human A3A (hA3A), one related to hA3C, and one related to hA3H. Both equine double-CDA proteins are similar to hA3F and were named eA3F1 and eA3F2. Analysis of eA3F1 and eA3F2 expression in vivo shows that the mRNAs encoding these proteins are widely expressed, including in cells that are natural EIAV targets. Both eA3F1 and eA3F2 inhibit retrotransposon mobility, while eA3F1 is a potent inhibitor of a Vif-deficient HIV-1 mutant and induces extensive editing of HIV-1 reverse transcripts. However, both eA3F1 and eA3F2 are weak inhibitors of EIAV. Surprisingly, eA3F1 and eA3F2 were packaged into EIAV and HIV-1 virions as effectively as hA3G, although only the latter inhibited EIAV infectivity. Moreover, all three proteins bound both the HIV-1 and EIAV nucleocapsid protein specifically in vitro. It therefore appears that EIAV has evolved a novel mechanism to specifically neutralize the biological activities of the cognate eA3F1 and eA3F2 proteins at a step subsequent to virion incorporation.