A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cells
A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cells
复制标题
DOI：
10.1016/s0960-9822(01)00373-6
复制
发表时间：
2001-08-21
期刊：
影响因子：
9.2
通讯作者：
Baur, AS
中科院分区：
文献类型：
--
作者：
Fackler, OT;Wolf, D;Baur, AS
在受感染的宿主中，HIV/SIV的Nef蛋白是高病毒载量所必需的，因此疾病进展[1-3]。最近的证据表明，在病毒从树突状细胞(DC)传播后，Nef增强了T细胞室的复制[4]。然而，潜在的机制尚不清楚。在这里，我们报告了富含脯氨酸基序(R71T)的自然变异深刻地调制了Nef刺激的未成熟树突状细胞/T细胞共培养的原代T细胞中的病毒复制。虽然两个Nef变异体(R/T-Nef)都下调了CD4，但只有支持病毒复制的异构体(R-Nef)能有效地与T细胞受体(TCR)环境中的信号分子相互作用，并刺激细胞激活。结构分析表明，R到T的转换引起构象变化，改变了含有PxxP基序的环的灵活性，从而改变了其结合细胞伙伴的能力。我们的报告表明，一旦病毒进入T细胞室，功能和构象上不同的Nef亚型在与TCR信号环境相互作用的水平上调节HIV的复制。
In the infected host, the Nef protein of HIV/SIV is required for high viral loads and thus disease progression [1-3]. Recent evidence indicates that Nef enhances replication in the T cell compartment after the virus is transmitted from dendritic cells (DC) [4]. The underlying mechanism, however, is not clear. Here, we report that a natural variability in the proline-rich motif (R71T) profoundly modulated Nef-stimulated viral replication in primary T cells of immature dendritic cell/T cell cocultures. Whereas both Nef variants (R/T-Nef) downregulated CD4, only the isoform supporting viral replication (R-Nef) efficiently interacted with signaling molecules of the T cell receptor (TCR) environment and stimulated cellular activation. Structural analysis suggested that the R to T conversion induces conformational changes, altering the flexibility of the loop containing the PxxP motif and hence its ability to bind cellular partners. Our report suggests that functionally and conformationally distinct Nef isoforms modulate HIV replication on the interaction level with the TCR-signaling environment once the virus enters the T cell compartment.