Chaudhry Ashutosh, Das Suman Ranjan, Hussain Amjad, Mayor Satyajit, George Anna, Bal Vineeta, Jameel Shahid, Rath Satyajit
National Institute of Immunology, New Delhi, India.
J Immunol. 2005 Oct 1;175(7):4566-74. doi: 10.4049/jimmunol.175.7.4566.
The Nef protein of HIV-1 is essential for its pathogenicity and is known to down-regulate MHC expression on infected cell surfaces. We now show that Nef also redistributes the costimulatory molecules CD80 and CD86 away from the cell surface in the human monocytic U937 cell line as well as in mouse macrophages and dendritic cells. Furthermore, HIV-1-infected U937 cells and human blood-derived macrophages show a similar loss of cell surface CD80 and CD86. Nef colocalizes with MHC class I (MHCI), CD80, and CD86 in intracellular compartments, and binds to both mouse and human CD80 and CD86. Some Nef mutants defective in MHCI down-modulation, including one from a clinical isolate, remain capable of down-modulating CD80 and CD86. Nef-mediated loss of surface CD80/CD86 is functionally significant, because it leads to compromised activation of naive T cells. This novel immunomodulatory role of Nef may be of potential importance in explaining the correlations of macrophage-tropism and Nef with HIV-1 pathogenicity and immune evasion.
HIV-1的Nef蛋白对其致病性至关重要，已知它会下调受感染细胞表面的MHC表达。我们现在发现，Nef还会使共刺激分子CD80和CD86从人单核细胞U937细胞系以及小鼠巨噬细胞和树突状细胞的细胞表面重新分布。此外，感染HIV-1的U937细胞和人血源性巨噬细胞也表现出类似的细胞表面CD80和CD86缺失。Nef与细胞内区室中的MHC I类（MHCI）、CD80和CD86共定位，并与小鼠和人类的CD80和CD86结合。一些在MHCI下调方面有缺陷的Nef突变体，包括一个来自临床分离株的突变体，仍然能够下调CD80和CD86。Nef介导的表面CD80/CD86缺失具有功能意义，因为它会导致初始T细胞的激活受损。Nef的这种新的免疫调节作用可能在解释巨噬细胞嗜性和Nef与HIV-1致病性及免疫逃逸的相关性方面具有潜在重要性。
