Multifaceted Counter-APOBEC3G Mechanisms Employed by HIV-1 Vif
Multifaceted Counter-APOBEC3G Mechanisms Employed by HIV-1 Vif
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DOI：
10.1016/j.jmb.2011.03.058
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发表时间：
2011-07-29
影响因子：
5.6
通讯作者：
Kotler, Moshe
中科院分区：
文献类型：
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作者：
Britan-Rosich, Elena;Nowarski, Roni;Kotler, Moshe
在缺乏人类免疫缺陷病毒1型（HIV-1）Vif蛋白的情况下，宿主抗病毒脱氨酶载脂蛋白B mRNA编辑酶催化多肽样3G（A3 G）通过逆转录产生的负单链DNA中的dC残基的脱氨基作用来限制感染性HIV-1的产生。Vif蛋白通过介导A3 G的蛋白酶体降解阻止A3 G包装成组装的病毒体来避免脱氨基的致命威胁。尽管Vif活性很强，但逃脱降解并掺入新组装的病毒体中的残留A3 G分子对病毒可能有害。我们假设病毒体相关的Vif抑制A3 G酶活性，从而防止新合成的病毒DNA的致死性诱变。在这里，我们表明，（i）从H9细胞释放的Vif-熟练的HIV-1颗粒含有A3 G与较低的比活性与Δ Vif病毒相关的A3 G相比，（ii）纯化的HIV-1 Vif抑制重组A3 G的脱氨活性，和（iii）纯化的HIV-1 Vif蛋白和Vif衍生肽Vif 25 -39抑制A3 G活性在体外以非竞争性的方式在纳摩尔浓度。我们的研究结果表明，潜在的Vif控制脱氨基的威胁，在病毒体或在前整合复合物进入靶细胞。因此，病毒体相关的Vif可以作为最后一道防线，保护病毒免受A3 G抗病毒活性的侵害。(C)2011爱思唯尔有限公司保留所有权利。
In the absence of human immunodeficiency virus type 1 (HIV-1) Vif protein, the host antiviral deaminase apolipoprotein B mRNA-editing enzymecatalytic polypeptide-like 3G (A3G) restricts the production of infectious HIV-1 by deamination of dC residues in the negative single-stranded DNA produced by reverse transcription. The Vif protein averts the lethal threat of deamination by precluding the packaging of A3G into assembling virions by mediating proteasomal degradation of A3G. In spite of this robust Vif activity, residual A3G molecules that escape degradation and incorporate into newly assembled virions are potentially deleterious to the virus. We hypothesized that virion-associated Vif inhibits A3G enzymatic activity and therefore prevents lethal mutagenesis of the newly synthesized viral DNA. Here, we show that (i) Vif-proficient HIV-1 particles released from H9 cells contain A3G with lower specific activity compared with Delta vif-virus-associated A3G, (ii) encapsidated HIV-1 Vif inhibits the deamination activity of recombinant A3G, and (iii) purified HIV-1 Vif protein and the Vif-derived peptide Vif25-39 inhibit A3G activity in vitro at nanomolar concentrations in an uncompetitive manner. Our results manifest the potentiality of Vif to control the deamination threat in virions or in the pre-integration complexes following entry to target cells. Hence, virion-associated Vif could serve as a last line of defense, protecting the virus against A3G antiviral activity. (C) 2011 Elsevier Ltd. All rights reserved.