Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE ε4/ε4 genotype accelerates HIV disease progression
Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE ε4/ε4 genotype accelerates HIV disease progression
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DOI：
10.1073/pnas.0803526105
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发表时间：
2008-06-24
影响因子：
11.1
通讯作者：
Ahuja, Sunil K.
中科院分区：
文献类型：
--
作者：
Burt, Trevor D.;Agan, Brian K.;Ahuja, Sunil K.
载脂蛋白（apo）E亚型（apoE 2、apoE 3和apoE 4）最初被认为在脂蛋白代谢和心血管疾病中起作用，但也被认为在与其脂质转运功能不直接相关的几种生物学过程中起关键作用。例如，apoE 4显著促进阿尔茨海默病中的神经变性。然而，apoE在感染性疾病中的作用尚不明确。在这里，通过检查一个大型队列的HIV（+）欧洲和非洲裔美国人的受试者，我们发现，APOE基因型与加速的疾病进程，尤其是与APOE基因型相比，APOE基因型与死亡的进展。然而，没有检测到HIV-4/HIV-4基因型与HIV相关性痴呆（HAD）（一种临床病理学特征类似于阿尔茨海默病的神经系统疾病）之间的关联。与观察到的基因型-表型关系一致，与重组apoE 3相比，apoE 4在体外增强了R5和X4 HIV毒株的HIV融合/细胞进入。这些发现确立了apoE作为HIV-AIDS发病机制的决定因素，并提出了目前将apoE 4转化为“apoE 3样”分子以治疗阿尔茨海默病的努力也可能在HIV疾病中具有临床适用性的可能性。
Originally recognized for their role in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E isoforms (apoE2, apoE3, and apoE4) have also been implicated to play a key role in several biological processes not directly related to their lipid transport function. For example, apoE4 contributes significantly to neurodegeneration in Alzheimer's disease. However, the role of apoE in infectious diseases is less well defined. Here, by examining a large cohort of HIV(+) European and African American subjects, we found that the APOE epsilon 4/epsilon 4 genotype is associated with an accelerated disease course and especially progression to death compared with the APOE epsilon 3/epsilon 3 genotype. However, an association between the epsilon 4/epsilon 4 genotype and HIV-associated dementia (HAD), a neurological condition with clinicopathological features similar to Alzheimer's disease, was not detected. Consistent with the genotype-phenotype relationships observed, compared with recombinant apoE3, apoE4 enhanced HlVfusion/cell entry of both R5 and X4 HIV strains in vitro. These findings establish apoE as a determinant of HIV-AIDS pathogenesis and raise the possibility that current efforts to convert apoE4 to an "apoE3-like" molecule to treat Alzheimer's disease might also have clinical applicability in HIV disease.