Macrophages are a reservoir for latent human immunodeficiency type 1 (HIV) infection and a barrier to HIV eradication. In contrast to CD4+ T cells, macrophages are resistant to the cytopathic effects of acute HIV infection. Emerging data suggest a role for TREM1 (triggering receptor expressed on myeloid cells 1) in this resistance to HIV-mediated cytopathogenesis. Here, we show that upon HIV infection, macrophages increase the expression of BCL2, BCLXL, TREM1, mitofusin 1 (MFN1), and MFN2 and the translocation of BCL2L11 (BIM) to the mitochondria and decrease the expression of BCL2-associated agonist of cell death (BAD) and BAX while maintaining a 95% survival rate over 28 days. The HIV proteins Tat and gp120 and the GU-rich single-stranded RNA (ssRNA) (RNA40) from the HIV long terminal repeat region (and a natural Toll-like receptor 8 [TLR8] agonist) induced similar effects. TREM1 silencing in HIV-infected macrophages led to decreased expression of BCL2, BCLXL, MFN1, and MFN2 and increased expression of BAD and BAX. This correlated with a significant increase in apoptosis mediated by a disruption of the mitochondrial membrane potential (Δψm), leading to the release of cytochrome c and caspase 9 cleavage. Exposure of TREM1-silenced macrophages to Tat, gp120, or RNA40 similarly resulted in the disruption of Δψm, cytochrome c release, caspase 9 cleavage, and apoptosis. Thus, our findings identify a mechanism whereby HIV promotes macrophage survival through TREM1-dependent upregulation of BCL2 family proteins and mitofusins that inhibits BCL2L11-mediated disruption of Δψm and subsequent apoptosis. These findings indicate that TREM1 can be a useful target for elimination of the HIV reservoir in macrophages.IMPORTANCE The major challenge to human immunodeficiency virus (HIV) treatment is the development of strategies that lead to viral eradication. A roadblock to accomplishing this goal is the lack of an approach that would safely eliminate HIV from all resting/latent reservoirs, including macrophages. Macrophages are a key part of the innate immune system and are responsible for recognizing invading microbes and sending appropriate signals to other immune cells. Here, we found that HIV induces the upregulation of the protein TREM1 (triggering receptor expressed on myeloid cells 1), which signals an increase in the expression of antiapoptotic proteins, thus promoting survival of HIV-infected macrophages.

中文翻译：

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TREM-1通过维持线粒体功能来保护HIV-1感染的巨噬细胞免于凋亡。

巨噬细胞是潜在的人类1型免疫缺陷病毒（HIV）潜在感染的储存库，也是消除HIV的障碍。与CD4 + T细胞相反，巨噬细胞对急性HIV感染的细胞病变作用有抵抗力。新兴数据表明，TREM1（在髓样细胞1上表达的触发受体）在这种对HIV介导的细胞病变的抗性中起着作用。在这里，我们表明，在HIV感染后，巨噬细胞会增加BCL2，BCLXL，TREM1，丝裂霉素1（MFN1）和MFN2的表达以及BCL2L11（BIM）向线粒体的转运，并降低与细胞BCL2相关的激动剂的表达死亡（BAD）和BAX，同时在28天内保持95％的存活率。HIV蛋白Tat和gp120以及来自HIV长末端重复区（和天然Toll样受体8 [TLR8]激动剂）的富含GU的单链RNA（ssRNA）（RNA40）诱导了相似的作用。TREM1沉默在HIV感染的巨噬细胞中导致BCL2，BCLXL，MFN1和MFN2的表达降低，以及BAD和BAX的表达增加。这与由线粒体膜电位（Δψm）破坏介导的细胞凋亡的显着增加相关，导致细胞色素c和caspase 9裂解的释放。TREM1沉默的巨噬细胞暴露于Tat，gp120或RNA40，同样会导致Δψm破坏，细胞色素c释放，胱天蛋白酶9裂解和凋亡。从而，我们的发现确定了一种机制，通过该机制，HIV通过抑制TCL1上调BCL2家族蛋白和丝裂霉素来促进巨噬细胞存活，从而抑制BCL2L11介导的Δψm破坏和随后的凋亡。这些发现表明，TREM1可能是消除巨噬细胞中的HIV蓄积的有用靶标。重要提示人类免疫缺陷病毒（HIV）治疗的主要挑战是制定可消除病毒的策略。实现这一目标的障碍是缺乏一种可以安全地从所有静止/潜在水库（包括巨噬细胞）中消除艾滋病毒的方法。巨噬细胞是先天免疫系统的关键部分，负责识别入侵的微生物并向其他免疫细胞发送适当的信号。这里，