Rhee S S, Marsh J W
Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD 20892.
J Immunol. 1994 May 15;152(10):5128-34.
Immediately after infection of the targeted cell by HIV-1, proviral gene expression is limited to the three regulatory proteins, Tat, Rev, and Nef, with the nef transcript representing nearly 80% of total expression. Additionally, simian immunodeficiency virus Nef has been shown to be essential for high in vivo titer and the development of immunodeficiency. Recent findings demonstrate that the negative effects of Nef expression, as first defined in transformed T cell lines, are not present when Nef is expressed in primary human T cells or in T cells from transgenic mice, in which one sees moderate positive enhancements of HIV replication and the T cell activation process, respectively. We find that Nef expression in an Ag-specific murine T cell hybridoma results in both the down-modulation of CD4, as seen in primary cells and human T cell lines, and a positive enhancement of the TCR response to stimuli. Examination of a CD4- cell demonstrated that the positive enhancement is independent of CD4 expression or modulation. CD4 down-modulation is shown to be caused by a post-Golgi, acid-dependent process, which dramatically decreases the lifespan of the CD4 molecule. The TCR, Thy Ag, and CD45 remained unchanged in their surface expression. These findings suggest that Nef alters the normal routing and residencies of the CD4 molecule and that the positive effect of Nef on T cell activation is independent of this modulation.
在HIV-1感染靶细胞后，原病毒基因表达仅限于三种调节蛋白，即Tat、Rev和Nef，其中nef转录本占总表达量的近80%。此外，猿猴免疫缺陷病毒Nef已被证明对高体内滴度和免疫缺陷的发展至关重要。最近的研究结果表明，Nef表达的负面影响，如最初在转化的T细胞系中所定义的，在原代人T细胞或转基因小鼠的T细胞中表达Nef时并不存在，在这些细胞中，分别观察到HIV复制和T细胞激活过程有适度的正向增强。我们发现，在抗原特异性小鼠T细胞杂交瘤中表达Nef会导致CD4的下调，这与原代细胞和人T细胞系中所见相同，同时也会使TCR对刺激的反应正向增强。对CD4 - 细胞的检查表明，正向增强与CD4的表达或调节无关。CD4下调被证明是由高尔基体后、酸依赖性过程引起的，这一过程显著缩短了CD4分子的寿命。TCR、Thy抗原和CD45的表面表达保持不变。这些发现表明，Nef改变了CD4分子的正常转运和驻留，并且Nef对T细胞激活的正向作用与这种调节无关。
