CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells.
CD4 Receptor is a Key Determinant of Divergent HIV-1 Sensing by Plasmacytoid Dendritic Cells.
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CD4受体是浆细胞样树突状细胞发散HIV-1传感的关键决定因素。
DOI：
10.1371/journal.ppat.1005553
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发表时间：
2016-04
期刊：
影响因子：
6.7
通讯作者：
Bhardwaj N
中科院分区：
文献类型：
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作者：
O'Brien M;Manches O;Wilen C;Gopal R;Huq R;Wu V;Sunseri N;Bhardwaj N
浆细胞样树突状细胞（Plasmacytoid dendritic cells，pDC）是一种先天性免疫细胞，其通过内体Toll样受体（TLR）7/9感知病毒核酸，产生I型干扰素（IFN）并分化为有效的抗原呈递细胞（antigen presenting cells，APC）。TLR 7/9在早期内体中的参与似乎触发IRF 7途径以产生IFN，而在溶酶体中的参与似乎触发NF-κB途径以成熟为APC。我们以前发现HIV-1（HIV）主要定位于早期内体，而不是溶酶体，并且主要刺激pDC中的IRF 7而不是NF-κB信号通路。这种不同的信号传导可能通过产生促凋亡和促炎IFN以及pDC的不充分成熟而导致疾病进展。我们现在证明，HIV病毒粒子可以通过流感病毒血凝素包膜假型HIV或修饰CD 4介导的细胞内运输重定向到溶酶体中进行NF-κB信号传导。这些数据表明，HIV包膜-CD 4受体相互作用驱动pDC活化为不成熟的产生IFN的表型，而不是分化为成熟的树突状细胞表型。浆细胞样树突状细胞（pDC）是专门产生I型干扰素（IFN）并激活适应性免疫应答的先天性免疫细胞。尽管干扰素是一种抗病毒细胞因子，但它可能对慢性病毒感染（包括慢性艾滋病毒感染）的发病机制贡献大于保护作用。pDC感受HIV后产生大量IFN，但产生的TNFα依赖于NF- κ B，共刺激分子的上调也很小，提示HIV促进pDC成为干扰素产生细胞（IPC）而不是抗原呈递细胞（APC）。在这里，我们使用流感病毒血凝素（HA）包膜假型化的流感病毒粒子和细胞系统表达的CD 4分子与修改的细胞内运输。我们发现用HA假型化的HIV病毒体刺激pDC成熟，类似于流感刺激的pDC，并且类似于流感在细胞内运输。我们还发现，CD 4介导的细胞内运输指导艾滋病毒的运输和下游信号。我们的研究提出了新的和重要的发现，证明了由pDC产生IFN而不是成为成熟的抗原呈递细胞的不同的HIV感测是由CD 4-HIV包膜相互作用特异性介导的。
Plasmacytoid dendritic cells (pDC) are innate immune cells that sense viral nucleic acids through endosomal Toll-like receptor (TLR) 7/9 to produce type I interferon (IFN) and to differentiate into potent antigen presenting cells (APC). Engagement of TLR7/9 in early endosomes appears to trigger the IRF7 pathway for IFN production whereas engagement in lysosomes seems to trigger the NF-κB pathway for maturation into APC. We showed previously that HIV-1 (HIV) localizes predominantly to early endosomes, not lysosomes, and mainly stimulate IRF7 rather than NF-κB signaling pathways in pDC. This divergent signaling may contribute to disease progression through production of pro-apoptotic and pro-inflammatory IFN and inadequate maturation of pDCs. We now demonstrate that HIV virions may be re-directed to lysosomes for NF-κB signaling by either pseudotyping HIV with influenza hemagglutinin envelope or modification of CD4 mediated-intracellular trafficking. These data suggest that HIV envelope-CD4 receptor interactions drive pDC activation toward an immature IFN producing phenotype rather than differentiation into a mature dendritic cell phenotype. Plasmacytoid dendritic cells (pDC) are innate immune cells that are specialized to produce type I interferon (IFN) and to activate adaptive immune responses. Although IFN is an anti-viral cytokine, it may contribute more to pathogenesis than to protection during chronic viral infections, including chronic HIV infection. pDC sense HIV to produce abundant IFN but minimal NF- κB–dependent production of TNFα and minimal up-regulation of co-stimulatory molecules, suggesting that HIV promotes pDC to become interferon producing cells (IPC) rather than antigen presenting cells (APC). Here, we use florescent HIV virions pseudotyped with influenza hemagglutinin (HA) envelope and a cell system expressing CD4 molecules with modified intracellular trafficking. We found that HIV virions pseudotyped with HA stimulate pDC to mature, similar to influenza-stimulated pDC, and traffic intracellularly similarly to influenza. We also find that CD4-mediated intracellular trafficking guides HIV trafficking and downstream signaling. Our study presents new and important findings which demonstrate that divergent HIV sensing by pDC to produce IFN, rather than to become mature antigen presenting cells, is mediated specifically by CD4-HIV envelope interactions.