Matheson Nicholas J, Sumner Jonathan, Wals Kim, Rapiteanu Radu, Weekes Michael P, Vigan Raphael, Weinelt Julia, Schindler Michael, Antrobus Robin, Costa Ana S H, Frezza Christian, Clish Clary B, Neil Stuart J D, Lehner Paul J
Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
Department of Infectious Diseases, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
Cell Host Microbe. 2015 Oct 14;18(4):409-23. doi: 10.1016/j.chom.2015.09.003. Epub 2015 Oct 1.
Critical cell surface immunoreceptors downregulated during HIV infection have previously been identified using non-systematic, candidate approaches. To gain a comprehensive, unbiased overview of how HIV infection remodels the T cell surface, we took a distinct, systems-level, quantitative proteomic approach. >100 plasma membrane proteins, many without characterized immune functions, were downregulated during HIV infection. Host factors targeted by the viral accessory proteins Vpu or Nef included the amino acid transporter SNAT1 and the serine carriers SERINC3/5. We focused on SNAT1, a β-TrCP-dependent Vpu substrate. SNAT1 antagonism was acquired by Vpu variants from the lineage of SIVcpz/HIV-1 viruses responsible for pandemic AIDS. We found marked SNAT1 induction in activated primary human CD4+ T cells, and used Consumption and Release (CoRe) metabolomics to identify alanine as an endogenous SNAT1 substrate required for T cell mitogenesis. Downregulation of SNAT1 therefore defines a unique paradigm of HIV interference with immunometabolism.
在HIV感染期间下调的关键细胞表面免疫受体此前已通过非系统性的候选方法得以鉴定。为了全面、无偏地了解HIV感染如何重塑T细胞表面，我们采用了一种独特的、系统层面的定量蛋白质组学方法。超过100种质膜蛋白在HIV感染期间被下调，其中许多蛋白的免疫功能尚未明确。病毒辅助蛋白Vpu或Nef靶向的宿主因子包括氨基酸转运体SNAT1和丝氨酸载体SERINC3/5。我们重点研究了SNAT1，一种依赖β-TrCP的Vpu底物。SNAT1拮抗作用是由来自导致大流行艾滋病的SIVcpz/HIV-1病毒谱系的Vpu变体获得的。我们发现活化的原代人CD4+T细胞中SNAT1显著诱导，并使用消耗与释放（CoRe）代谢组学来确定丙氨酸是T细胞有丝分裂所需的内源性SNAT1底物。因此，SNAT1的下调定义了HIV干扰免疫代谢的一种独特模式。
