Remarkable Lethal G-to-A Mutations in vif-Proficient HIV-1 Provirus by Individual APOBEC3 Proteins in Humanized Mice
Remarkable Lethal G-to-A Mutations in vif-Proficient HIV-1 Provirus by Individual APOBEC3 Proteins in Humanized Mice
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DOI：
10.1128/jvi.00823-10
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发表时间：
2010-09-15
影响因子：
5.4
通讯作者：
Koyanagi, Yoshio
中科院分区：
文献类型：
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作者：
Sato, Kei;Izumi, Taisuke;Koyanagi, Yoshio
包括人类免疫缺陷病毒1型（HIV-1）在内的RNA病毒的基因组超突变可由内在和外在压力引起，这导致病毒复制的抑制和/或病毒多样性的进展。人APOBEC 3G被鉴定为HIV-1限制因子，其通过诱导G至A超突变来编辑新生HIV-1 DNA并削弱vif缺陷型HIV-1的感染性。另一方面，HIV-1 Vif蛋白具有降解APOBEC 3G蛋白的强大潜力。虽然随后的研究表明，APOBEC 3家族蛋白具有突变HIV-1 DNA的能力，但仍不清楚这些内源性APOBEC 3，包括APOBEC 3G，是否有助于体内vif-熟练的HIV-1前病毒的突变，如果是这样，这些突变的意义是什么。在这项研究中，我们使用人造血干细胞移植的人源化小鼠（NOG-hCD 34小鼠）模型，并证明了G-to-A突变在vif-proficient HIV-1前病毒中的主要积累，显示出APOBEC 3介导的诱变特征。值得注意的是，显著观察到导致翻译终止的HIV-1 DNA的APOBEC 3相关G至A突变。我们进一步提供了一个新的见解，表明HIV-1 G到A的超突变是由单个APOBEC 3蛋白独立诱导的。与细胞内前病毒DNA的显著突变相反，血浆中的病毒RNA具有较少的G至A突变。综上所述，这些结果提供了证据表明内源性APOBEC 3与体内HIV-1前病毒的G至A突变相关，这可以导致HIV-1感染的消除。
Genomic hypermutation of RNA viruses, including human immunodeficiency virus type 1 (HIV-1), can be provoked by intrinsic and extrinsic pressures, which lead to the inhibition of viral replication and/or the progression of viral diversity. Human APOBEC3G was identified as an HIV-1 restriction factor, which edits nascent HIV-1 DNA by inducing G-to-A hypermutations and debilitates the infectivity of vif-deficient HIV-1. On the other hand, HIV-1 Vif protein has the robust potential to degrade APOBEC3G protein. Although subsequent investigations have revealed that lines of APOBEC3 family proteins have the capacity to mutate HIV-1 DNA, it remains unclear whether these endogenous APOBEC3s, including APOBEC3G, contribute to mutations of vif-proficient HIV-1 provirus in vivo and, if so, what is the significance of these mutations. In this study, we use a human hematopoietic stem cell-transplanted humanized mouse (NOG-hCD34 mouse) model and demonstrate the predominant accumulation of G-to-A mutations in vif-proficient HIV-1 provirus displaying characteristics of APOBEC3-mediated mutagenesis. Notably, the APOBEC3-associated G-to-A mutation of HIV-1 DNA that leads to the termination of translation was significantly observed. We further provide a novel insight suggesting that HIV-1 G-to-A hypermutation is independently induced by individual APOBEC3 proteins. In contrast to the prominent mutation in intracellular proviral DNA, viral RNA in plasma possessed fewer G-to-A mutations. Taken together, these results provide the evidence indicating that endogenous APOBEC3s are associated with G-to-A mutation of HIV-1 provirus in vivo, which can result in the abrogation of HIV-1 infection.