Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins.
Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins.
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DOI：
10.1371/journal.ppat.1000181
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发表时间：
2008-10
期刊：
影响因子：
6.7
通讯作者：
Bieniasz PD
中科院分区：
文献类型：
--
作者：
Perez-Caballero D;Soll SJ;Bieniasz PD
由于逆转录病毒偶发性定域所施加的进化压力，许多哺乳动物表达诸如TRIM5α和APOBEC3蛋白等直接限制逆转录病毒复制的因子。TRIM5和apobecc限制因子最常在现代灵长类慢病毒的背景下进行研究，但很可能是古代逆转录病毒施加了灵长类TRIM5和APOBEC3基因中明显的选择压力。此外，这些抗逆转录病毒因子已被证明对多种逆转录病毒起作用，包括γ -逆转录病毒。内源性逆转录病毒可以提供已灭绝逆转录病毒的“化石记录”，也可能是古代TRIM5和APOBEC3抗病毒活性的证据。在这里，我们研究了TRIM5和APOBEC3蛋白是否限制了过去几百万年内源性的两组γ -逆转录病毒的复制。这些内源性逆转录病毒在旧大陆灵长类动物的基因组中相当普遍，但未能在人类生殖系中定植。我们的分析表明，TRIM5α蛋白不会对这两种病毒科的跨物种传播构成主要障碍，也不会导致它们的灭绝。然而，我们发现了大量证据表明，通过APOBEC3胞苷脱氨酶的作用，古γ -逆转录病毒失活。有趣的是，负责失活的胞苷脱氨酶的特性似乎在病毒和宿主物种依赖的方式上有所不同。总的来说，从保存在现代生物体基因组中的残体中对古代逆转录病毒进行序列分析和重组，为探索和潜在地解释宿主对逆转录病毒防御的进化史提供了机会。逆转录病毒将其基因组整合到宿主细胞DNA中，作为其复制周期的重要组成部分。如果逆转录病毒被整合到一个细胞中，成为生殖系细胞，如精子或卵子，那么它可能被遗传为“内源性”逆转录病毒。事实上，内源性逆转录病毒在哺乳动物DNA中非常普遍，约占人类DNA的8%。这些内源性逆转录病毒大多来自现已灭绝的古老病毒。在这项研究中，我们恢复了两组灭绝的逆转录病毒的部分，其中许多菌株在过去的几百万年里被整合到许多非人灵长类动物的基因组中，但在人类DNA中缺失。我们能够通过将已灭绝病毒的一部分插入到在小鼠中发现的现代逆转录病毒中来产生传染性逆转录病毒，并通过这样做能够从功能上分析已灭绝病毒的特性。结合这些功能分析和序列分析，我们获得了证据，证明现代灵长类动物中存在的一些快速进化的宿主防御分子能够抑制这些已灭绝病毒的复制。因此，特定的宿主防御可能限制了古代逆转录病毒在物种之间的传播，并可能导致它们的灭绝。
Because of evolutionary pressures imposed through episodic colonization by retroviruses, many mammals express factors, such as TRIM5α and APOBEC3 proteins, that directly restrict retroviral replication. TRIM5 and APOBEC restriction factors are most often studied in the context of modern primate lentiviruses, but it is likely that ancient retroviruses imposed the selective pressure that is evident in primate TRIM5 and APOBEC3 genes. Moreover, these antiretroviral factors have been shown to act against a variety of retroviruses, including gammaretroviruses. Endogenous retroviruses can provide a ‘fossil record’ of extinct retroviruses and perhaps evidence of ancient TRIM5 and APOBEC3 antiviral activity. Here, we investigate whether TRIM5 and APOBEC3 proteins restricted the replication of two groups of gammaretroviruses that were endogenized in the past few million years. These endogenous retroviruses appear quite widespread in the genomes of old world primates but failed to colonize the human germline. Our analyses suggest that TRIM5α proteins did not pose a major barrier to the cross-species transmission of these two families of gammaretroviruses, and did not contribute to their extinction. However, we uncovered extensive evidence for inactivation of ancient gammaretroviruses through the action of APOBEC3 cytidine deaminases. Interestingly, the identities of the cytidine deaminases responsible for inactivation appear to have varied in both a virus and host species–dependent manner. Overall, sequence analyses and reconstitution of ancient retroviruses from remnants that have been preserved in the genomes of modern organisms offer the opportunity to probe and potentially explain the evolutionary history of host defenses against retroviruses. Retroviruses integrate their genomes into host-cell DNA as an essential part of their replication cycle. If a retrovirus is integrated into a cell that becomes a germ line cell such as a sperm or an egg, then it may be inherited as an ‘endogenous’ retrovirus. In fact, endogenous retroviruses are extraordinarily common in mammalian DNA, constituting about 8% of human DNA. These endogenous retroviruses are mostly derived from ancient viruses that are now extinct. In this study, we recovered parts of two groups of extinct retroviruses, many strains of which became integrated into genomes of many nonhuman primates over the past few million years, but are absent from human DNA. We were able to generate infectious retroviruses by inserting a part of the extinct viruses into a modern retrovirus found in mice, and in so doing were able to functionally analyze properties of the extinct virus. Using a combination of these functional analyses, as well as sequence analysis, we obtained evidence that some rapidly evolving host defense molecules present in modern primates were able to inhibit the replication of these extinct viruses. Therefore, particular host defenses may have limited transmission of ancient retroviruses between species and perhaps contributed to their extinction.
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