CD4-Dependent Modulation of HIV-1 Entry by LY6E.
CD4-Dependent Modulation of HIV-1 Entry by LY6E.
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LY6E 对 HIV-1 进入的 CD4 依赖性调节。
DOI：
10.1128/jvi.01866-18
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发表时间：
2019
影响因子：
5.4
通讯作者：
Liu,Shan-Lu
中科院分区：
文献类型：
--
作者：
Yu,Jingyou;Liang,Chen;Liu,Shan-Lu
淋巴细胞抗原6 E（LY 6 E）是一种GPI锚定的干扰素诱导蛋白，已显示以细胞类型依赖性方式调节病毒感染。我们最近的工作表明，LY 6 E促进HIV-1感染一些高表达CD 4的细胞，包括人外周血单核细胞（PBMC）和SupT 1细胞系。在这项工作中，我们提供的证据表明，LY 6 E通过下调病毒受体CD 4抑制HIV-1进入和传播低CD 4表达的Jurkat细胞和人单核细胞衍生的巨噬细胞（MDM）。我们发现Jurkat细胞和MDM中LY 6 E的敲低增加了HIV-1感染，而Jurkat细胞中LY 6 E的过表达抑制了HIV-1的进入和复制。发现LY 6 E与Jurkat细胞和MDM的质膜上的CD 4共定位并且增强CD 4内化。我们人工操纵Jurkat和SupT 1细胞中的CD 4水平，发现Jurkat细胞中CD 4的过表达克服了LY 6 E的抑制作用;相反，用中和抗体阻断SupT 1中CD 4的功能消除了LY 6 E对HIV-1进入的增强作用。LY 6 E在低CD 4表达的人MDM中的CD 4依赖性抑制表型可以重现为一组传播的创始者病毒和实验室适应的HIV-1毒株。鉴于HIV-1在急性感染期间可以靶向低CD 4表达细胞，但在疾病晚期在高CD 4表达T细胞中有效复制，我们观察到LY 6 E以CD 4依赖性方式差异调节HIV-1复制，这对于理解干扰素（IFN）诱导的蛋白质在艾滋病发病机制中的复杂作用具有重要意义。在病毒感染中的作用还不完全清楚。虽然大多数ISG是抗病毒的，但一些ISG已被证明可促进病毒感染，包括HIV-1感染。我们以前的研究表明，干扰素诱导的LY 6 E蛋白促进HIV-1感染人外周血单个核细胞和高表达CD 4的SupT 1细胞。在这里，我们发现LY 6 E抑制HIV-1在低CD 4表达的MDM和Jurkat细胞中的进入和复制。从机制上讲，我们证明了LY 6 E下调细胞表面受体CD 4，从而削弱了病毒与靶细胞的结合。这与高CD 4表达细胞的情况相反，其中LY 6 E主要促进病毒膜融合。IFN诱导的LY 6 E在调节HIV-1感染中的相反作用突出了ISG在病毒感染和病毒发病机制中的复杂作用。
Lymphocyte antigen 6E (LY6E) is a GPI-anchored, interferon-inducible protein that has been shown to modulate viral infection in a cell type-dependent manner. Our recent work showed that LY6E promotes HIV-1 infection in some high-CD4-expressing cells, including human peripheral blood mononuclear cells (PBMCs) and the SupT1 cell line. In this work, we provide evidence that LY6E inhibits HIV-1 entry and spread in low-CD4-expressing Jurkat cells and human monocyte-derived macrophages (MDMs) through downregulation of the viral receptor CD4. We found that knockdown of LY6E in Jurkat cells and MDMs increases HIV-1 infection, yet overexpression of LY6E in Jurkat cells inhibits HIV-1 entry and replication. LY6E was found to be colocalized with CD4 on the plasma membrane of Jurkat cells and MDMs and enhances CD4 internalization. We artificially manipulated the CD4 level in Jurkat and SupT1 cells and found that overexpression of CD4 in Jurkat cells overcomes the inhibitory effect of LY6E; conversely, blocking the function of CD4 in SupT1 with a neutralizing antibody eliminates the enhancement of LY6E on HIV-1 entry. The CD4-dependent inhibitory phenotype of LY6E in low-CD4-expressing human MDMs can be recapitulated for a panel of transmitted founder viruses and laboratory-adapted HIV-1 strains. Given that HIV-1 can target low-CD4-expressing cells during acute infection yet replicates efficiently in high-CD4-expressing T cells at the late stage of disease, our observation that LY6E differentially modulates HIV-1 replication in a CD4-dependent manner has implications for understanding the complex roles of interferon (IFN)-induced proteins in AIDS pathogenesis.IMPORTANCEThe role of IFN-induced genes (ISGs) in viral infection remains incompletely understood. While most ISGs are antiviral, some ISGs have been shown to promote viral infection, including HIV-1 infection. We previously showed that IFN-inducible LY6E protein promotes HIV-1 infection in human PMBCs and high-CD4-expressing SupT1 cells. Here we found that LY6E inhibits HIV-1 entry and replication in low-CD4-expressing MDMs and Jurkat cells. Mechanistically, we demonstrated that LY6E downregulates the cell surface receptor CD4, thus impairing the virus binding to target cells. This is in contrast to the situation of high-CD4-expressing cells, where LY6E predominantly promotes viral membrane fusion. The opposing role of IFN-inducible LY6E in modulating HIV-1 infection highlights the complex roles of ISGs in viral infection and viral pathogenesis.