Rate of killing of HIV-infected T cells and disease progression
Rate of killing of HIV-infected T cells and disease progression
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DOI：
10.1126/science.272.5270.1962
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发表时间：
1996-06-28
期刊：
影响因子：
56.9
通讯作者：
Neumann, AU
中科院分区：
文献类型：
--
作者：
Huynen, MA;Neumann, AU
Steven M. Wolinsky 等人 (1)（我们中的一位 AUN 是该研究的合著者）最近进行的一项研究发现，在 6 名感染人类免疫缺陷病毒 (HIV) 的个体中，一些生物学参数与疾病进展速度相关。 CD4 细胞快速耗竭和疾病进展与抗 HIV 溶细胞 T 淋巴细胞 (CTL) 前体频率低、病毒载量高以及遗传多样性病毒形式的缓慢积累有关。有人建议 (1, 2) 这些措施可以用免疫系统杀死受感染细胞的有效性来解释，并且成功的免疫压力导致了 HIV 的适应性进化。观察到的与疾病进展的另一个相关性是，与快速进展者中的剪接 mRNA 相比，未剪接的细胞 HIV 信使 RNA (mRNA) 占优势。目前的假设表明 (3) 观察到的患者中未剪接与剪接 RNA 比率（U/S RNA 比率）的差异是由于患者携带具有不同病毒特性的病毒所致。剪接与未剪接 RNA 比率的差异也可能是由细胞免疫反应有效性的差异来解释。受感染细胞产生 HIV RNA 会经历几个阶段。在早期阶段，病毒转录物经过多重剪接以表达早期调控基因，并且不会从细胞核中输出未剪接的 RNA。仅在病毒表达的后期，未剪接的 RNA 才会被输出到细胞质 (4)。因此，U/S RNA 比率强烈依赖于仅表达剪接 RNA 的早期细胞与也表达未剪接 RNA 的晚期细胞的比率。在早期阶段更快地杀死细胞不会改变 U/S RNA 比率，因为后期的细胞数量取决于完成早期表达阶段的细胞数量。因此，如果更多的早期细胞被杀死，剪接和未剪接的细胞内mRNA的量将成比例地减少。另一方面，在后期表达阶段更快地杀死细胞将显着重新
In a recent study by Steven M. Wolinsky et al.(1), of which one of us, AUN, was a co-author, several biological parameters were found to be associated with the rate of disease progression in six individuals infected with human immunodeficiency virus (HIV). Rapid CD4 cell depletion and disease progression was associated with low anti-HIV cytolytic T lymphocyte (CTL) precursor frequency, high viral loads, and slow accumulation of genetically diverse vi-ral forms. It was suggested (1, 2) that these measures could be explained by the effectiveness of the immune system in killing infected cells, and that a successful immune pressure resulted in adaptive evolution of HIV. An additional correlation with disease progression that was observed was a preponderance of unspliced cellular HIV messen-ger RNA (mRNA) as compared to spliced mRNA in rapid progressors. Current hypotheses suggest (3) that the observed differences in the ratio of unspliced to spliced RNA (U/S RNA ratio) among patients is accounted for by the patients having viruses with different viral properties.The difference in the ratio of spliced to unspliced RNA might also be explained by differences in the effectiveness of the cellular immune response. HIV RNA production by an infected cell goes through several phases. In the early phase the viral transcript gets multiply spliced to express the early regulatory genes and there is no export of unspliced RNA from the nucleus. Only in the late phase of viral expression does unspliced RNA getexported to the cytoplasm (4). The U/S RNA ratio is therefore strongly dependent on the ratio of cells in the early phase, expressing only spliced RNA, versus the cells in the late phase, expressing also unspliced RNA. Faster killing of the cells in the early phase will not change the U/S RNA ratio, because the number of cells in the laterphase depends on the number of cells thatcomplete the early expression phase. Thus, if more early phase cells are killed, the amounts of both spliced and unspliced intracellular mRNA will be reduced proportionately. On the other hand, faster killing of the cells in the later expression phase will significantly re-