Differences in APOBEC3G expression in CD4+ T helper lymphocyte subtypes modulate HIV-1 infectivity.
Differences in APOBEC3G expression in CD4+ T helper lymphocyte subtypes modulate HIV-1 infectivity.
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DOI：
10.1371/journal.ppat.1000292
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发表时间：
2009-02
期刊：
影响因子：
6.7
通讯作者：
D'Aquila, Richard T.
中科院分区：
文献类型：
--
作者：
Vetter, Michael L.;Johnson, Megan E.;Antons, Amanda K.;Unutmaz, Derya;D'Aquila, Richard T.
胞苷脱氨酶APOBEC 3G和APOBEC 3F发挥抗HIV-1活性，该活性被HIV-1 vif蛋白抵消。基于潜在的转录因子结合位点在其假定的启动子，我们假设，表达的APOBEC 3G和APOBEC 3F将随T辅助淋巴细胞分化。通过转录因子Tbet和GATA 3的表达以及细胞因子极化，幼稚CD 4 + T淋巴细胞分化为辅助性T细胞1型（Th 1）和2型（Th 2）效应细胞。APOBEC 3G和APOBEC 3F RNA水平以及APOBEC 3G蛋白水平在Th 1细胞中高于Th 2细胞。T细胞受体刺激进一步增加Tbet和对照转导的细胞中的APOBEC 3G和APOBEC 3F表达，但在GATA 3转导的细胞中不增加。中和抗干扰素-γ抗体降低了Tbet和对照转导细胞中基础和T细胞受体刺激的APOBEC 3G和APOBEC 3F表达。与Th 2细胞产生的病毒粒子相比，Th 1细胞产生的HIV-1具有更多的病毒粒子APOBEC 3G，并且降低了感染性。Th 1和Th 2产生的病毒体之间的这些差异对于缺乏功能性vif的病毒更大，但也见于vif阳性病毒。APOBEC 3G在Th 2细胞中的过表达降低了Th 2细胞产生的病毒体的感染性，而APOBEC 3G在Th 1细胞中的减少增加了Th 1细胞产生的病毒体的感染性，这与APOBEC 3G在感染性差异中的因果作用一致。这些结果表明，APOBEC 3G和APOBEC 3F水平在CD 4 + T淋巴细胞分化过程中发生生理变化，干扰素-γ有助于这种调节，并且这种生理调节可导致子代病毒粒子感染性的变化，即使在存在HIV-1 vif的情况下。一些宿主细胞蛋白可以阻碍或限制HIV-1的生命周期。APOBEC 3G和APOBEC 3F是细胞酶，如果它们存在于病毒颗粒中，则会降低HIV-1在随后的靶细胞中复制的能力。作为对策，HIV-1病毒粒子感染因子（vif）诱导APOBEC 3G和APOBEC 3F的降解，从而防止它们进入出芽病毒。尽管vif缺陷型病毒无法逃避APOBEC 3G的抗病毒作用，但此类病毒很少存在于HIV-1感染的人类中。目前尚不清楚CD 4 + T淋巴细胞中APOBEC 3G和APOBEC 3F表达的生理变化是否足以降低vif阳性HIV-1感染性。在这项研究中，我们发现T辅助1型（Th 1）细胞，一种CD 4+淋巴细胞的亚型，比T辅助2型（Th 2）细胞表达更大量的APOBEC 3G和APOBEC 3F。这种差异导致了从两种细胞类型产生的HIV-1感染性的差异，无论vif是否表达。这些结果表明，APOBEC 3G的生理调节确实限制了vif阳性的HIV-1，以及vif阴性的HIV-1。此外，这项研究揭示了调节这些蛋白质表达的生物学因素，这些蛋白质可能可用于针对HIV-1的新的治疗或预防策略。
The cytidine deaminases APOBEC3G and APOBEC3F exert anti–HIV-1 activity that is countered by the HIV-1 vif protein. Based on potential transcription factor binding sites in their putative promoters, we hypothesized that expression of APOBEC3G and APOBEC3F would vary with T helper lymphocyte differentiation. Naive CD4+ T lymphocytes were differentiated to T helper type 1 (Th1) and 2 (Th2) effector cells by expression of transcription factors Tbet and GATA3, respectively, as well as by cytokine polarization. APOBEC3G and APOBEC3F RNA levels, and APOBEC3G protein levels, were higher in Th1 than in Th2 cells. T cell receptor stimulation further increased APOBEC3G and APOBEC3F expression in Tbet- and control-transduced, but not in GATA3-transduced, cells. Neutralizing anti–interferon-γ antibodies reduced both basal and T cell receptor-stimulated APOBEC3G and APOBEC3F expression in Tbet- and control-transduced cells. HIV-1 produced from Th1 cells had more virion APOBEC3G, and decreased infectivity, compared to virions produced from Th2 cells. These differences between Th1- and Th2-produced virions were greater for viruses lacking functional vif, but also seen with vif-positive viruses. Over-expression of APOBEC3G in Th2 cells decreased the infectivity of virions produced from Th2 cells, and reduction of APOBEC3G in Th1 cells increased infectivity of virions produced from Th1 cells, consistent with a causal role for APOBEC3G in the infectivity difference. These results indicate that APOBEC3G and APOBEC3F levels vary physiologically during CD4+ T lymphocyte differentiation, that interferon-γ contributes to this modulation, and that this physiological regulation can cause changes in infectivity of progeny virions, even in the presence of HIV-1 vif. Some host cell proteins can hinder, or restrict, the life cycle of HIV-1. APOBEC3G and APOBEC3F are cellular enzymes that decrease HIV-1's ability to replicate in a subsequent target cell if they are present in the virus particle. As a countermeasure, HIV-1 virion infectivity factor (vif) induces degradation of APOBEC3G and APOBEC3F, thereby preventing them from getting into the budding virus. Although vif-defective viruses cannot evade the antiviral effect of APOBEC3G, such viruses are very rarely present in HIV-1-infected humans. It is not yet known whether physiological variation in APOBEC3G and APOBEC3F expression in CD4+ T lymphocytes is substantial enough to reduce vif-positive HIV-1 infectivity. In this study, we found that T helper type 1 (Th1) cells, a subtype of CD4+ lymphocytes, expressed greater amounts of APOBEC3G and APOBEC3F than T helper type 2 (Th2) cells. This difference led to a difference in infectivity of HIV-1 produced from the two cell types, whether vif was expressed or not. These results demonstrate that physiological regulation of APOBEC3G does restrict vif-positive HIV-1, as well as vif-negative HIV-1. In addition, this study reveals biological factors regulating expression of these proteins that may be exploitable for new therapeutic or preventive strategies against HIV-1.
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