National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
PLoS One. 2011 Apr 5;6(4):e18291. doi: 10.1371/journal.pone.0018291.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) could induce apoptosis of HIV-1-infected monocyte-derived macrophage (MDM), but the molecular mechanisms are not well understood.
METHODOLOGY/PRINCIPAL FINDINGS: By using an HIV-1 Env-pseudotyped virus (HIV-1 PV)-infected MDM cell model we demonstrate that HIV-1 PV infection down-regulates the expression of TRAIL decoy receptor 1 (DcR1) and 2 (DcR2), and cellular FLICE-inhibitory protein (c-FLIP), but dose not affect the expression of death receptor 4 and 5 (DR4, DR5), and Bcl-2 family members in MDM cells. Furthermore, recombinant soluble TRAIL and an agonistic anti-DR5 antibody, AD5-10, treatment stimulates reactive oxygen species (ROS) generation and JNK phosphorylation.
CONCLUSIONS/SIGNIFICANCE: HIV infection facilitates TRIAL-induced cell death in MDM by down-regulating the expression of TRAIL decoy receptors and intracellular c-FLIP. Meanwhile, the agonistic anti-DR5 antibody, AD5-10, induces apoptosis synergistically with TRAIL in HIV-1-infected cells. ROS generation and JNK phosphorylation are involved in this process. These findings potentiate clinical usage of the combination of TRAIL and AD5-10 in eradication of HIV-infected macrophage and AIDS.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）可诱导 HIV-1 感染的单核细胞衍生巨噬细胞（MDM）凋亡，但分子机制尚不清楚。
方法/主要发现：我们通过使用 HIV-1 包膜假型病毒（HIV-1 PV）感染的 MDM 细胞模型证明，HIV-1 PV 感染下调 TRAIL 诱饵受体 1（DcR1）和 2（DcR2）以及细胞 FLICE 抑制蛋白（c-FLIP）的表达，但不影响 MDM 细胞中死亡受体 4 和 5（DR4、DR5）以及 Bcl-2 家族成员的表达。此外，重组可溶性 TRAIL 和激动型抗 DR5 抗体 AD5-10 处理可刺激活性氧（ROS）生成和 JNK 磷酸化。
结论/意义：HIV 感染通过下调 TRAIL 诱饵受体和细胞内 c-FLIP 的表达，促进 MDM 中 TRAIL 诱导的细胞死亡。同时，激动型抗 DR5 抗体 AD5-10 与 TRAIL 协同诱导 HIV-1 感染细胞凋亡。ROS 生成和 JNK 磷酸化参与了这一过程。这些发现促进了 TRAIL 和 AD5-10 的联合使用，以清除 HIV 感染的巨噬细胞和艾滋病。
