Inhibition of HIV Replication by Apolipoprotein A-I Binding Protein Targeting the Lipid Rafts
Inhibition of HIV Replication by Apolipoprotein A-I Binding Protein Targeting the Lipid Rafts
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DOI：
10.1128/mbio.02956-19
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发表时间：
2020-01-01
期刊：
影响因子：
6.4
通讯作者：
Bukrinsky, Michael
中科院分区：
文献类型：
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作者：
Dubrovsky, Larisa;Ward, Adam;Bukrinsky, Michael
载脂蛋白A-I结合蛋白（AIBP）是一种参与调节脂筏和胆固醇流出的蛋白质。AIBP已被认为在与脂筏丰度增加相关的几组病理条件下起保护因子的作用，如动脉粥样硬化和急性肺损伤。在这里，我们表明，外源性AIBP减少了丰富的脂筏和抑制HIV复制在体外以及在HIV感染的人源化小鼠，而敲低内源性AIBP增加HIV复制。内源性AIBP在活化的T细胞中比在单核细胞衍生的巨噬细胞（MDM）中丰富得多，而外源性AIBP在T细胞中比在MDM中有效得多。AIBP抑制病毒-细胞融合，特异性靶向具有通过细胞活化动员的脂筏或含Nef的外泌体的细胞。MDM-HIV融合体仅在病毒或外泌体提供的Nef存在下对AIBP敏感。来自HLA-B * 35基因型供体的外周血单核细胞与HIV疾病的快速进展相关，与来自其他HLA基因型供体的细胞相比，AIBP结合较少，并且不受AIBP的保护以防止HIV-1的快速复制。这些结果提供了Nef外泌体通过修饰脂筏调节HIV-细胞融合的作用的第一个证据，并表明AIBP是一种通过靶向脂筏限制HIV复制的先天性因子。重要信息载脂蛋白A-I结合蛋白（AIBP）是最近鉴定的先天性抗炎因子。在这里，我们发现AIBP通过靶向脂筏和减少病毒-细胞融合来抑制HIV复制。重要的是，AIBP选择性地降低了由炎症刺激刺激或用含有HIV-1蛋白Nef的细胞外囊泡处理的细胞上的筏的水平，而不影响非活化细胞上的筏。因此，单核细胞衍生的巨噬细胞与HIV的融合只有在Nef存在的情况下才对AIBP敏感。内源性AIBP的沉默显著上调HIV-1复制。有趣的是，来自HLA-B * 35基因型供体的细胞中的HIV-1复制（与HIV疾病的快速进展相关）并不受AIBP的抑制。这些结果表明，AIBP是一种天然的抗HIV因子，靶向病毒-细胞融合。
Apolipoprotein A-I binding protein (AIBP) is a protein involved in regulation of lipid rafts and cholesterol efflux. AIBP has been suggested to function as a protective factor under several sets of pathological conditions associated with increased abundance of lipid rafts, such as atherosclerosis and acute lung injury. Here, we show that exogenously added AIBP reduced the abundance of lipid rafts and inhibited HIV replication in vitro as well as in HIV-infected humanized mice, whereas knockdown of endogenous AIBP increased HIV replication. Endogenous AIBP was much more abundant in activated T cells than in monocyte-derived macrophages (MDMs), and exogenous AIBP was much less effective in T cells than in MDMs. AIBP inhibited virus-cell fusion, specifically targeting cells with lipid rafts mobilized by cell activation or Nef-containing exosomes. MDM-HIV fusion was sensitive to AIBP only in the presence of Nef provided by the virus or exosomes. Peripheral blood mononuclear cells from donors with the HLA-B*35 genotype, associated with rapid progression of HIV disease, bound less AIBP than cells from donors with other HLA genotypes and were not protected by AIBP from rapid HIV-1 replication. These results provide the first evidence for the role of Nef exosomes in regulating HIV-cell fusion by modifying lipid rafts and suggest that AIBP is an innate factor that restricts HIV replication by targeting lipid rafts.IMPORTANCE Apolipoprotein A-I binding protein (AIBP) is a recently identified innate anti-inflammatory factor. Here, we show that AIBP inhibited HIV replication by targeting lipid rafts and reducing virus-cell fusion. Importantly, AIBP selectively reduced levels of rafts on cells stimulated by an inflammatory stimulus or treated with extracellular vesicles containing HIV-1 protein Nef without affecting rafts on nonactivated cells. Accordingly, fusion of monocyte-derived macrophages with HIV was sensitive to AIBP only in the presence of Nef. Silencing of endogenous AIBP significantly upregulated HIV-1 replication. Interestingly, HIV-1 replication in cells from donors with the HLA-B*35 genotype, associated with rapid progression of HIV disease, was not inhibited by AIBP. These results suggest that AIBP is an innate anti-HIV factor that targets virus-cell fusion.