Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice

The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depletion of human leukocytes, including CD4 T cells. We developed a monoclonal antibody that specifically depletes human pDC in all lymphoid organs in humanized mice. When pDC were depleted prior to HIV-1 infection, the induction of IFN-I and interferon-stimulated genes (ISGs) were abolished during acute HIV-1 infection with either a highly pathogenic CCR5/CXCR4-dual tropic HIV-1 or a standard CCR5-tropic HIV-1 isolate. Consistent with the anti-viral role of IFN-I, HIV-1 replication was significantly up-regulated in pDC-depleted mice. Interestingly, the cell death induced by the highly pathogenic HIV-1 isolate was severely reduced in pDC-depleted mice. During chronic HIV-1 infection, depletion of pDC also severely reduced the induction of IFN-I and ISGs, associated with elevated HIV-1 replication. Surprisingly, HIV-1 induced depletion of human immune cells including T cells in lymphoid organs, but not the blood, was reduced in spite of the increased viral replication. The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells. We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis. These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment.

浆细胞样树突状细胞（plasmacytoid dendritic cells，pDC）在人类免疫缺陷病毒1型（human immunodeficiency virus type 1，HIV-1）感染与发病机制中的作用仍未明确。人源化小鼠模型（humanized mouse model）中的HIV-1感染可导致持续性HIV-1感染及免疫病理损伤，包括I型干扰素（type I interferons，IFN-I）激活、免疫活化以及包括CD4 T细胞（CD4 T cells）在内的人类白细胞（human leukocytes）耗竭。本研究制备了一种单克隆抗体（monoclonal antibody），可在人源化小鼠的所有淋巴器官中特异性耗竭人类pDC。若在HIV-1感染前耗竭pDC，无论是高致病性CCR5/CXCR4双嗜性HIV-1毒株还是标准CCR5嗜性HIV-1分离株感染的急性期，IFN-I与干扰素刺激基因（interferon-stimulated genes，ISGs）的诱导表达均被完全阻断。与IFN-I的抗病毒作用一致，pDC耗竭小鼠体内的HIV-1复制水平显著上调。有趣的是，高致病性HIV-1分离株诱导的细胞死亡在pDC耗竭小鼠中显著减轻。在慢性HIV-1感染阶段，pDC耗竭同样显著降低了IFN-I及ISGs的诱导表达，并伴随HIV-1复制水平升高。令人意外的是，尽管病毒复制水平有所升高，但HIV-1诱导的淋巴器官（而非血液）内包括T细胞在内的人类免疫细胞耗竭现象却得到缓解。淋巴器官内细胞数的增加，与包括CD4 T细胞在内的人类白细胞的HIV诱导细胞死亡水平降低密切相关。本研究得出结论：pDC在抑制HIV-1复制与促进HIV-1诱导的免疫病理损伤这两个方面发挥着相互对立的作用。上述研究结果提示，pDC耗竭与IFN-I阻断策略将为那些尽管接受了有效抗逆转录病毒治疗但仍存在持续性免疫活化的HIV-1免疫无应答患者提供全新的治疗手段。