Independent evolution of an antiviral TRIMCyp in rhesus macaques
Independent evolution of an antiviral TRIMCyp in rhesus macaques
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DOI：
10.1073/pnas.0709003105
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发表时间：
2008-03-04
影响因子：
11.1
通讯作者：
Towers, Greg J.
中科院分区：
文献类型：
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作者：
Wilson, Sam J.;Webb, Benjamin L. J.;Towers, Greg J.
抗逆转录病毒限制因子 TRIMS 最近已成为哺乳动物先天免疫和逆转录病毒复制的物种特异性抑制的重要介质。来自病原体感染的选择压力推动了 TRIMS 基因的快速进化，导致了我们今天看到的抗病毒特异性。值得注意的是，新大陆鸮猴 (Aotus trivirgatus) 编码 TRIMS 蛋白，其中 B30.2 结构域中的抗病毒决定簇已被逆转录转座 cDNA 编码的亲环蛋白 A (CypA) 取代。猫头鹰猴 TRIMCyp 蛋白限制慢病毒子集的感染，这些慢病毒将 CypA 募集到其衣壳中，包括 HIV-1 和猫免疫缺陷病毒。在这里，我们发现旧世界猴子恒河猴（Macaca mulatta）也编码一种独立于猫头鹰猴中产生的 TRIMCyp 蛋白。恒河猴 TRIMCyp 由恒河猴 TRIMS 基因的一个单一但常见的等位基因 (Mamu7) 编码，该等位基因是编码与 CypA 没有同源性的全长 TRIMS 蛋白的至少六个等位基因之一。恒河猴 TRIMCyp 的抗病毒特异性非常明显，可以限制 HIV-2 和猫免疫缺陷病毒的感染，但不能限制 HIV-1 的感染。恒河猴 TRIMCyp 的限制发生在逆转录之前，并通过用环孢菌素 A 阻断 CypA 结合或通过衣壳 CypA 结合位点的突变来抑制。这些观察结果表明 TRIMCyp 蛋白之间存在保守的限制机制。缺乏针对 HIV-1 的活性表明 Mamu7 纯合动物对于 TRIMS 介导的 HIV-1 限制无效，并且可能有助于改进 HIV/AIDS 动物模型。
The antiretroviral restriction factor TRIMS has recently emerged as an important mediator of innate immunity and species-specific inhibition of retroviral replication in mammals. Selection pressure from pathogenic infection has driven rapid evolution of TRIMS genes, leading to the antiviral specificities we see today. Remarkably, the New World owl monkey (Aotus trivirgatus) encodes a TRIMS protein in which the antiviral determinants in the B30.2 domain have been replaced by cyclophilin A (CypA) encoded by a retrotransposed cDNA. The owl monkey TRIMCyp protein restricts infection by a subset of lentiviruses that recruit CypA to their capsids, including HIV-1 and feline immunodeficiency virus. Here, we show that the Old World monkey, rhesus macaque (Macaca mulatta), also encodes a TRIMCyp protein that has arisen independently from that in owl monkeys. The rhesus TRIMCyp is encoded by a single, but common, allele (Mamu7) of the rhesus TRIMS gene, among at least six further alleles that encode full-length TRIMS proteins with no homology to CypA. The antiviral specificity of the rhesus TRIMCyp is distinct, restricting infection of HIV-2 and feline immunodeficiency virus but not HIV-1. Restriction by rhesus TRIMCyp is before reverse transcription and inhibited by blocking CypA binding, with cyclosporine A, or by mutation of the capsid CypA binding site. These observations suggest a mechanism of restriction that is conserved between TRIMCyp proteins. The lack of activity against HIV-1 suggests that Mamu7 homozygous animals will be null for TRIMS-mediated restriction of HIV-1 and could contribute to improved animal models for HIV/AIDS.