DRAM Triggers Lysosomal Membrane Permeabilization and Cell Death in CD4+ T Cells Infected with HIV

Productive HIV infection of CD4+ T cells leads to a caspase-independent cell death pathway associated with lysosomal membrane permeabilization (LMP) and cathepsin release, resulting in mitochondrial outer membrane permeabilization (MOMP). Herein, we demonstrate that HIV infection induces damage-regulated autophagy modulator (DRAM) expression in a p53-dependent manner. Knocking down the expression of DRAM and p53 genes with specific siRNAs inhibited autophagy and LMP. However, inhibition of Atg5 and Beclin genes that prevents autophagy had a minor effect on LMP and cell death. The knock down of DRAM gene inhibited cytochrome C release, MOMP and cell death. However, knocking down DRAM, we increased viral infection and production. Our study shows for the first time the involvement of DRAM in host-pathogen interactions, which may represent a mechanism of defense via the elimination of infected cells.CD4阳性T细胞的产性HIV感染会触发一条与溶酶体膜通透性改变（lysosomal membrane permeabilization, LMP）和组织蛋白酶释放相关的半胱天冬酶非依赖性细胞死亡通路，最终引发线粒体外膜通透性改变（mitochondrial outer membrane permeabilization, MOMP）。本研究证实，HIV感染可通过p53依赖的方式诱导损伤调控自噬调节因子（damage-regulated autophagy modulator, DRAM）的表达。利用特异性小干扰RNA（siRNAs）敲低DRAM与p53的基因表达，能够抑制自噬与LMP的发生。然而，阻断可抑制自噬的Atg5基因与Beclin基因的表达，却仅对LMP及细胞死亡产生微弱影响。敲低DRAM基因可抑制细胞色素C的释放、MOMP以及细胞死亡，但与此同时，敲低DRAM会增强病毒的感染与复制能力。本研究首次揭示了DRAM在宿主-病原体互作中的参与作用，这可能代表了一种通过清除受感染细胞以实现宿主防御的机制。