Inhibition of HIV-1 Infection and Replication by Enhancing Viral Incorporation of Innate Anti-HIV-1 Protein A3G A NON-PATHOGENIC Nef MUTANT-BASED ANTI-HIV STRATEGY
Inhibition of HIV-1 Infection and Replication by Enhancing Viral Incorporation of Innate Anti-HIV-1 Protein A3G A NON-PATHOGENIC Nef MUTANT-BASED ANTI-HIV STRATEGY
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DOI：
10.1074/jbc.m806631200
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发表时间：
2009-05-15
影响因子：
4.8
通讯作者：
He, Johnny J.
中科院分区：
文献类型：
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作者：
Green, Linden A.;Liu, Ying;He, Johnny J.
APOBEC 3G（A3 G）是一种细胞蛋白，已被鉴定为先天性抗人类免疫缺陷病毒1型（HIV-1）因子。HIV-1病毒体感染性蛋白（Vif）的主要功能之一是靶向A3 G进行泛素化/蛋白酶体介导的降解，从而逃避宿主的先天防御机制。因此，我们希望设计一种策略，通过主动将A3 G靶向HIV-1病毒体并对抗HIV-1 Vif靶向降解来恢复A3 G的抗HIV活性。在目前的研究中，我们使用A3 G作为递送载体对该策略进行了一系列概念验证实验，A3 G是非致病性Nef突变体Nef 7的衍生物，能够有效地掺入HIV-1病毒体中。我们证明了Nef 7。A3 G融合蛋白保留了Nef 7的几个重要特性，即更高的病毒粒子掺入效率，无PAK-2（p21激活激酶2）激活，无CD 4和主要组织相容性复合体I下调。同时，我们表明，病毒粒子纳入Nef 7。A3 G具有A3 G的抗HIV感染功能。此外，我们表明，病毒样颗粒介导的反向融合传递Nef 7。A3 G进入HIV感染的CD 4 + T淋巴细胞导致这些细胞中HIV-1复制的有效抑制。综上所述，这些结果表明Nef 7. A3 G可以通过恢复A3 G的病毒体掺入来有效地限制HIV感染和复制，即使在存在Vif的情况下。
APOBEC3G (A3G) is a cellular protein that has been identified as an innate anti-human immunodeficiency virus type 1 (HIV-1) factor. One of the major functions of HIV-1 virion infectivity protein (Vif) protein is to target A3G for ubiquitination/proteasome-mediated degradation and, as a result, evade the host innate defense mechanism. Thus, we wished to devise a strategy to restore the anti-HIV activity of A3G by actively targeting it into HIV-1 virions and countering HIV-1 Vif-targeted degradation. In the current study we performed a series of proof-of-concept experiments for this strategy using as a delivery vehicle of A3G, a derivate of non-pathogenic Nef mutant Nef7 that is capable of being efficiently incorporated into HIV-1 virions. We demonstrate that the Nef7. A3G fusion protein retains several important properties of Nef7; that is, the higher virion incorporation efficiency, no PAK-2 (p21-activated kinase 2) activation, and no CD4 and major histocompatibility complex I down-regulation. Meanwhile, we show that virion incorporated Nef7. A3G possesses the anti-HIV infectivity function of A3G. Moreover, we show that virus-like particle-mediated inverse fusion delivery of Nef7. A3G into HIV-infected CD4+ T lymphocytes leads to potent inhibition of HIV-1 replication in these cells. Taken together, these results indicate that Nef7. A3G can effectively restrict HIV infection and replication by restoring the virion incorporation of A3G, even in the presence of Vif.