Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells (Retracted Article. See vol 466, pg 276, 2010)
Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells (Retracted Article. See vol 466, pg 276, 2010)
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DOI：
10.1038/nature03493
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发表时间：
2005-05-05
期刊：
影响因子：
64.8
通讯作者：
Greene, WC
中科院分区：
文献类型：
--
作者：
Chiu, YL;Soros, VB;Greene, WC
与活化的CD 4（+）T细胞相反，血液中循环的静息人CD 4（+）T细胞对人免疫缺陷病毒（HIV）感染具有高度抗性（1-4）。HIV无法感染这些静止的CD 4（+）T细胞是由于缺乏关键因子，还是反映了有效的防御HIV的机制，目前尚不清楚。我们发现抗逆转录病毒脱氧胞苷脱氨酶APOBEC 3G（5）能有效保护未受刺激的外周血CD 4（+）T细胞免受HIV-1感染。在活化的CD 4（+）T细胞中，胞质APOBEC 3G存在于一种无酶活性的高分子量（HMM）核糖核蛋白复合物中，该复合物在用RNA酶处理后转化为有酶活性的低分子量（LMM）形式。相反，LMM APOBEC 3G在未刺激的CD 4（+）T细胞中占主导地位，其中HIV-1复制被阻断，逆转录受损（1-3）。有丝分裂原活化诱导LMM APOBEC 3G募集到HMM复合物中，这与这些受刺激细胞中HIV感染的百分比急剧增加相关。值得注意的是，当APOBEC 3G特异性小干扰RNA被引入未受刺激的CD 4（+）T细胞时，HIV-1遇到的早期复制阻断被大大缓解。因此，LMM APOBEC 3G在未刺激的CD 4（+）T细胞中作为HIV-1的有效进入后限制因子发挥作用。令人惊讶的是，对未受刺激的CD 4（+）T细胞中缓慢形成的逆转录物进行测序，仅显示低水平的dG -> dA超突变，这增加了APOBEC 3G限制活性可能不严格依赖于脱氧胞苷脱氨基的可能性。
In contrast to activated CD4(+) T cells, resting human CD4(+) T cells circulating in blood are highly resistant to infection with human immunodeficiency virus (HIV)(1-4). Whether the inability of HIV to infect these resting CD4(+) T cells is due to the lack of a key factor, or alternatively reflects the presence of an efficient mechanism for defence against HIV, is not clear. Here we show that the anti-retroviral deoxycytidine deaminase APOBEC3G(5) strongly protects unstimulated peripheral blood CD4(+) T cells against HIV-1 infection. In activated CD4(+) T cells, cytoplasmic APOBEC3G resides in an enzymatically inactive, high-molecular-mass (HMM) ribonucleoprotein complex that converts to an enzymatically active low-molecular-mass (LMM) form after treatment with RNase. In contrast, LMM APOBEC3G predominates in unstimulated CD4(+) T cells, where HIV-1 replication is blocked and reverse transcription is impaired(1-3). Mitogen activation induces the recruitment of LMM APOBEC3G into the HMM complex, and this correlates with a sharp increase in permissivity for HIV infection in these stimulated cells. Notably, when APOBEC3G-specific small interfering RNAs are introduced into unstimulated CD4(+) T cells, the early replication block encountered by HIV-1 is greatly relieved. Thus, LMM APOBEC3G functions as a potent post-entry restriction factor for HIV-1 in unstimulated CD4(+) T cells. Surprisingly, sequencing of the reverse transcripts slowly formed in unstimulated CD4(+) T cells reveals only low levels of dG --> dA hypermutation, raising the possibility that the APOBEC3G-restricting activity may not be strictly dependent on deoxycytidine deamination.