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首页> 外文期刊>Current Biology: CB >High-frequency persistence of an impaired allele of the retroviral defense gene TRIM5 alpha in humans
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High-frequency persistence of an impaired allele of the retroviral defense gene TRIM5 alpha in humans

机译：逆转录病毒防御基因TRIM5 alpha受损等位基因在人类中的高频持久性

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摘要

The intracellular TRIM5 alpha protein successfully inhibits HIV-1 infection in rhesus monkeys, but not in humans [1-6]. A few amino acids in the virus-interacting SPRY domain [7] were found to be responsible for most of this anti-viral specificity [8-10], raising the possibility that genetic variation among humans could result in TRIM5 alpha proteins with a spectrum of potencies. We found several nonsynonymous SNPs at the human TRIM5 locus, but only one of these (H43Y) was found to have a significant functional consequence. We demonstrate that H43Y impairs TRIM5 alpha restriction of two distantly related retroviruses. H43Y lies in the RING domain of TRIM5 alpha and may negatively affect its putative E3 ubiquitin ligase activity. This detrimental allele dates back to before the African diaspora and is found at a frequency of 43% in indigenous Central and South Americans. We suggest that relaxed constraint due to a recent period of low retroviral challenge has allowed the deleterious H43Y mutation to persist and even to expand after the bottleneck that occurred upon human migration to the New World. The unexpectedly high frequency of an impaired retroviral restriction allele among humans is likely to have a significant impact on our ability to ward off future retroviral challenges.
机译：细胞内的TRIM5α蛋白成功地抑制了猕猴的HIV-1感染，但对人类没有抑制作用[1-6]。发现与病毒相互作用的SPRY结构域中的一些氨基酸[7]负责大部分这种抗病毒特异性[8-10]，从而增加了人类之间的遗传变异可能导致具有光谱的TRIM5α蛋白的可能性。效力。我们在人类TRIM5基因座上发现了几个非同义SNP，但仅发现其中一个（H43Y）具有重要的功能后果。我们证明，H43Y损害TRIM5 alpha限制的两个远距离相关的逆转录病毒。 H43Y位于TRIM5 alpha的RING域中，可能会对它的推定E3泛素连接酶活性产生负面影响。这种有害的等位基因可以追溯到非洲人散居之前，在中美洲和南美土著中发现的频率为43％。我们建议，由于最近一段时间的低逆转录病毒攻击而导致的宽松约束已使有害的H43Y突变在人类迁徙到新大陆后出现瓶颈后得以持续甚至扩展。人类中逆转录病毒限制性等位基因异常高发生的频率异常高，可能会对我们抵御未来逆转录病毒挑战的能力产生重大影响。

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