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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion.
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A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion.

机译：人APOBEC3G抗逆转录病毒酶中的单个氨基酸取代赋予对HIV-1病毒体感染性因子诱导的耗竭的抗性。

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摘要

HIV-1 and other retroviruses occasionally undergo hypermutation, characterized by a high rate of G-to-A substitution. Recently, the human apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G), first identified as CEM15, was shown to be packaged into retroviral virions and to deaminate deoxycytidine to deoxyuridine in newly synthesized viral minus-strand DNA, thereby inducing G-to-A hypermutation. This innate mechanism of resistance to retroviral infection is counteracted by the HIV-1 viral infectivity factor (Vif), which protects the virus by preventing the incorporation of APOBEC3G into virions by rapidly inducing its ubiquitination and proteasomal degradation. To gain insights into the mechanism by which Vif protects HIV-1 from APOBEC3G, we substituted several amino acids in human APOBEC3G with equivalent residues in simian APOBEC3Gs that are resistant to HIV-1 Vif and determined the effects of the mutations on HIV-1 replication in the presence and absence of Vif. We found that a single amino acid substitution mutant of human APOBEC3G (D128K) can interact with HIV-1 Vif but is not depleted from cells; thus, it inhibits HIV-1 replication in an HIV-1 Vif-resistant manner. Interestingly, rhesus macaque simian immunodeficiency virus 239 or HIV-2 Vif coexpression depleted the intracellular steady state levels of the D128K mutant and abrogated its antiviral activity, indicating that it can be a substrate for the proteasomal pathway. The HIV-1 Vif-resistant mutant APOBEC3G could provide a gene therapy approach to combat HIV-1 infection.
机译：HIV-1和其他逆转录病毒偶尔会发生超突变，其特征是G-to-A替换率很高。最近，首次鉴定为CEM15的人类载脂蛋白B mRNA编辑，酶催化，多肽样3G（APOBEC3G）被包装到逆转录病毒颗粒中，并在新合成的病毒负链DNA中将脱氧胞苷脱氨为脱氧尿苷，从而诱导G-to-A超变。 HIV-1病毒感染因子（Vif）抵消了这种对逆转录病毒感染的固有机制，该因子通过迅速诱导泛素化和蛋白酶体降解来防止APOBEC3G掺入病毒颗粒中，从而保护了病毒。为了深入了解Vif保护HIV-1免受APOBEC3G侵害的机制，我们用猿猴APOBEC3Gs中对HIV-1 Vif有抗性的等效残基替换了人类APOBEC3G中的几个氨基酸，并确定了这些突变对HIV-1复制的影响在存在和不存在Vif的情况下。我们发现人类APOBEC3G（D128K）的单个氨基酸取代突变体可以与HIV-1 Vif相互作用，但不会从细胞中耗尽。因此，它以抗HIV-1 Vif的方式抑制HIV-1复制。有趣的是，猕猴猿猴免疫缺陷病毒239或HIV-2 Vif共表达耗尽了D128K突变体的细胞内稳态水平，并废除了其抗病毒活性，表明它可以是蛋白酶体途径的底物。耐HIV-1 Vif的突变体APOBEC3G可以提供对抗HIV-1感染的基因治疗方法。

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