Virion encapsidated HIV-1 Vpr induces NFAT to prime non-activated T cells for productive infection.
Virion encapsidated HIV-1 Vpr induces NFAT to prime non-activated T cells for productive infection.
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DOI：
10.1098/rsob.160046
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发表时间：
2016-07
期刊：
影响因子：
5.8
通讯作者：
Schindler M
中科院分区：
文献类型：
--
作者：
Höhne K;Businger R;van Nuffel A;Bolduan S;Koppensteiner H;Baeyens A;Vermeire J;Malatinkova E;Verhasselt B;Schindler M
HIV-1遇到的大多数T细胞是非活化的，不容易进行生产性感染。HIV-1 Vpr在子代病毒体中高度丰富，并诱导信号传导和HIV-1 LTR转录。因此，我们假设Vpr可能是非活化T细胞感染的决定因素。病毒体递送的Vpr通过Ca 2+内流和干扰活化T细胞的核因子（NFAT）输出激酶GSK 3 β来活化NFAT。这导致NFAT在细胞核内易位和积累，并且是未刺激的原代CD 4 + T细胞的生产性感染所需的。诱变方法揭示了Vpr介导的NFAT活化与其增强LTR转录和介导细胞周期停滞的能力的相关性。NFAT抑制后，Vpr没有增加静息T细胞感染，并显示减少G2/M停滞和LTR反式激活。总而言之，Vpr使未受刺激的T细胞对生产性HIV-1感染更宽容，并刺激生产性感染以及病毒暴露的T细胞的活化。因此，它可能参与HIV-1从病毒库的建立和重新激活，并可能对免疫激活水平产生影响，这是HIV-1发病机制的决定因素。
The majority of T cells encountered by HIV-1 are non-activated and do not readily allow productive infection. HIV-1 Vpr is highly abundant in progeny virions, and induces signalling and HIV-1 LTR transcription. We hence hypothesized that Vpr might be a determinant of non-activated T-cell infection. Virion-delivered Vpr activated nuclear factor of activated T cells (NFAT) through Ca2+ influx and interference with the NFAT export kinase GSK3β. This leads to NFAT translocation and accumulation within the nucleus and was required for productive infection of unstimulated primary CD4+ T cells. A mutagenesis approach revealed correlation of Vpr-mediated NFAT activation with its ability to enhance LTR transcription and mediate cell cycle arrest. Upon NFAT inhibition, Vpr did not augment resting T-cell infection, and showed reduced G2/M arrest and LTR transactivation. Altogether, Vpr renders unstimulated T cells more permissive for productive HIV-1 infection and stimulates activation of productively infected as well as virus-exposed T cells. Therefore, it could be involved in the establishment and reactivation of HIV-1 from viral reservoirs and might have an impact on the levels of immune activation, which are determinants of HIV-1 pathogenesis.