Human cytidine deaminase APOBEC3H restricts HIV-1 replication
Human cytidine deaminase APOBEC3H restricts HIV-1 replication
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DOI：
10.1074/jbc.m707586200
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发表时间：
2008-04-25
影响因子：
4.8
通讯作者：
Zheng, Yong-Hui
中科院分区：
文献类型：
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作者：
Dang, Ying;Siew, Lai Mun;Zheng, Yong-Hui
人类基因组编码7种具有潜在抗逆转录病毒活性的APOBEC3 （A3）胞苷脱氨酶：A3A、A3B、A3C、A3DE、A3F、A3G和A3H。A3G是第一个被发现能够阻断人类免疫缺陷病毒1型（HIV-1）和许多其他逆转录病毒复制的药物。后来发现A3F、A3B和A3DE具有相似的活性。HIV-1产生一种叫做Vif的蛋白质，它能够中和A3DE、A3F和A3G的抗逆转录病毒活性，但不能中和A3B。由于A3H在细胞培养中表达较差，因此其抗逆转录病毒活性尚待确定。我们研究了A3H表达受损的机制。在比较灵长类动物的A3H序列时，在人类和黑猩猩的A3H基因的第5外显子上发现了一个过早终止密码子，该密码子显著降低了它们的蛋白表达。它会导致C端缺失29个残基，这种截断不会降低人A3H蛋白的稳定性。然而，截断基因的mRNA水平显著降低。人A3H蛋白的表达可以通过修复这种截断或通过含有人巨细胞病毒内含子的载体表达恢复到正常水平。一旦优化表达，人A3H可以将HIV-1的传染性降低150倍。重要的是，HIV-1 Vif不能中和A3H活性。然而，广泛的序列分析无法检测到人类A3H在HIV-1基因组中有任何显著水平的G-to-A突变。因此，A3H通过胞苷脱氨无关的机制有效地抑制HIV-1复制，优化A3H在体内的表达可能代表一种新的HIV-1治疗策略。
The human genome encodes seven APOBEC3 (A3) cytidine deaminases with potential antiretroviral activity: A3A, A3B, A3C, A3DE, A3F, A3G, and A3H. A3G was the first identified to block replication of human immunodeficiency virus type 1 (HIV-1) and many other retroviruses. A3F, A3B, and A3DE were shown later to have similar activities. HIV-1 produces a protein called Vif that is able to neutralize the antiretroviral activities of A3DE, A3F, and A3G, but not A3B. Only the antiretroviral activity of A3H remains to be defined due to its poor expression in cell culture. Here, we studied the mechanism impairing A3H expression. When primate A3H sequences were compared, a premature termination codon was identified on the fifth exon of the human and chimpanzee A3H genes, which significantly decreased their protein expression. It causes a 29-residue deletion from the C terminus, and this truncation did not reduce human A3H protein stability. However, the mRNA levels of the truncated gene were significantly decreased. Human A3H protein expression could be restored to a normal level either by repairing this truncation or through expression from a vector containing an intron from human cytomegalovirus. Once expression was optimized, human A3H could reduce HIV-1 infectivity up to 150-fold. Importantly, HIV-1 Vif failed to neutralize A3H activity. Nevertheless, extensive sequence analysis could not detect any significant levels of G-to-A mutation in the HIV-1 genome by human A3H. Thus, A3H inhibits HIV-1 replication potently by a cytidine deamination-independent mechanism, and optimizing A3H expression in vivo should represent a novel therapeutic strategy for HIV-1 treatment.