近日，有两个实验室分别对此分子机制进行了深入研究，同时在Nature发文，发现Nef蛋白通过下调细胞表面分子SERINC3和SERINC5，阻碍其整合到病毒粒子中，从而提高HIV-1的感染力。一篇是由美国麻省大学医学院Heinrich G. Göttlinger教授实验室完成。Göttlinger教授小组根据Nef和glycoGag蛋白在HIV-1感染内吞过程中的重要性，推测Nef和glycoGag蛋白可能下调了某种整合到病毒粒子中的限制性因子。通过对纯化正常病毒（Nef+）、Nef缺失病毒（Nef-）和glycoGag替换Nef病毒（glycoMA）进行蛋白质组学分析，最后鉴别出了Nef-病毒粒子中特异性存在的宿主细胞蛋白SERINC3。另一篇由意大利特伦托大学Massimo Pizzato教授领导的合作小组完成。Pizzato教授小组比较了正常病毒（Nef+）和Nef缺失病毒（Nef-）在31种人类细胞系中的感染性差异，在这些细胞系中病毒感染的程度有所差异，最后通过比较强弱细胞中转录组分析，鉴别出SERINC5基因与Nef蛋白相关。
本文由中国病毒学论坛原创，欢迎转载，转载请注明出处。 作者: ipsvirus 时间: 2015-10-8 18:57 SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef
Yoshiko Usami, Yuanfei Wu & Heinrich G. Göttlinger
HIV-1 Nef and the unrelated mouse leukaemia virus glycosylated Gag (glycoGag) strongly enhance the infectivity of HIV-1 virions produced in certain cell types in a clathrin-dependent manner. Here we show that Nef and glycoGag prevent the incorporation of the multipass transmembrane proteins serine incorporator 3 (SERINC3) and SERINC5 into HIV-1 virions to an extent that correlates with infectivity enhancement. Silencing of both SERINC3 and SERINC5 precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. The infectivity of nef-deficient virions increased more than 100-fold when produced in double-knockout human CD4+ T cells that lack both SERINC3 and SERINC5, and re-expression experiments confirmed that the absence of SERINC3 and SERINC5 accounted for the infectivity enhancement. Furthermore, SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. SERINC3 and SERINC5 are highly expressed in primary human HIV-1 target cells, and inhibiting their downregulation by Nef is a potential strategy to combat HIV/AIDS.
Annachiara Rosa, Ajit Chande, Serena Ziglio, Veronica De Sanctis, Roberto Bertorelli, Shih Lin Goh, Sean M. McCauley, Anetta Nowosielska, Stylianos E. Antonarakis, Jeremy Luban, Federico Andrea Santoni & Massimo Pizzato
HIV-1 Nef, a protein important for the development of AIDS, has well-characterized effects on host membrane trafficking and receptor downregulation. By an unidentified mechanism, Nef increases the intrinsic infectivity of HIV-1 virions in a host-cell-dependent manner. Here we identify the host transmembrane protein SERINC5, and to a lesser extent SERINC3, as a potent inhibitor of HIV-1 particle infectivity that is counteracted by Nef. SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. Nef redirects SERINC5 to a Rab7-positive endosomal compartment and thereby excludes it from HIV-1 particles. The ability to counteract SERINC5 was conserved in Nef encoded by diverse primate immunodeficiency viruses, as well as in the structurally unrelated glycosylated Gag from murine leukaemia virus. These examples of functional conservation and convergent evolution emphasize the fundamental importance of SERINC5 as a potent anti-retroviral factor.
Nef is a small protein of the HIV virus that performs several diverse tasks during infection. It reduces the expression of a variety of proteins on the surface of the infected cell (usually, T cells of the host's immune system), modulates T-cell signalling pathways, and increases the infectivity of new virus particles released from the cell. But for more than two decades, the mechanism by which Nef achieves this last function has been poorly understood. Now, in two breakthrough studies in this issue, Rosa et al.1 (page 212) and Usami et al.2 (page 218) show that Nef prevents the action of two host proteins previously not known to have antiviral activity: SERINC3 and SERINC5.
http://www.nature.com/nature/jou ... ll/nature15637.html作者: ipsvirus 时间: 2015-10-8 19:10
此外，10月1号在Cell host & Microbe上也online了一篇文章报道了SERINC3和SERINC5分子的发现。来自剑桥大学的Nicholas J. Matheson和 Paul J. Lehner教授通过对T细胞表面蛋白组学分析，分别测试了HIV-1的Vpu和Nef蛋白分别造成的影响，其中就有Nef关系的SERINC3和SERINC5分子，此外还有一个Vpu相关的新分子SNAT1。
Cell Surface Proteomic Map of HIV Infection Reveals Antagonism of Amino Acid Metabolism by Vpu and Nef
Nicholas J. Matheson, Jonathan Sumner, Kim Wals, Radu Rapiteanu, Michael P. Weekes, Raphael Vigan, Julia Weinelt, Michael Schindler, Robin Antrobus, Ana S.H. Costa, Christian Frezza, Clary B. Clish, Stuart J.D. Neil, Paul J. Lehner
Highlights
•Unbiased global analysis of T cell surface proteome remodeling during HIV infection
•>100 proteins downregulated, including Nef targets SERINC3/5 and Vpu target SNAT1
•β-TrCP-dependent SNAT1 downregulation acquired by pandemic SIVcpz/HIV-1 viruses
•Uptake of exogenous alanine by SNAT1 critical for primary CD4+ T cell mitogenesis
Summary
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.