HIV-1感染巨噬细胞后可导致部分细胞死亡，但机制未明。我们前期电镜结果发现，HIV-1感染可导致人单核细胞源巨噬细胞(MDMs)死亡，呈现典型的铁死亡特征，而且HIV上调的p53表达很可能涉及其中。本项目采用MDMs和THP-1源巨噬细胞两种HIV-1体外感染模型，通过加入铁离子或铁离子螯合剂确认HIV-1诱导铁死亡的发生，再对p53进行表达干预（敲降表达/过表达）确定其在HIV-1诱导铁死亡中的中介作用，并通过不同铁死亡通路诱导剂或抑制剂确定p53调控的主要铁死亡通路和作用的关键因子，进一步采用CHIP-qPCR、EMSA、荧光素酶报告基因分析等确定p53作用的靶基因，并对靶基因表达干预，最终阐明p53介导HIV-1诱导巨噬细胞铁死亡的分子机制。预期研究结果可为HIV-1感染导致巨噬细胞死亡提出新机制，为HIV-1感染致病机理提供新认识，也为巨噬细胞作为HIV储存库的清除提供新策略。

HIV-1 infection of macrophages can cause death of partial cells, however, the mechanism(s) is still unclear. Our preliminary results using electron microscopy showed that HIV-1 infection could cause the death of human monocyte-derived macrophages (MDMs), presenting the typical characteristics of ferroptosis. And the up-regulated p53 expression by HIV-1 infection is likely to be involved in this process. This project will adopt MDMs and THP-1 macrophages as two in vitro HIV-1 infection models. Firstly, the occurrence of HIV-1-induced ferroptosis will be confirmed by adding ferrrous fumarate or deferoxamine to the virus-cell cultures. And then expression intervention on p53 (silencing expression/over-expression) in macrophages will be used to determine the mediation role of p53 in HIV-1-induced ferroptosis. Combined p53 expression intervention with the use of various inducers or inhibitors on different ferroptosis pathways, we will determine the major ferroptosis pathway regulated by p53 and the key ferroptosis factors for its action, Furthermore, CHIP-qPCR, EMSA, and luciferase reporter gene analysis will be used to determine the target genes of p53. Finally, expression intervention on identified p53-targeted genes will be carried out to elucidate the molecular mechanism(s) of p53-mediated HIV-1-induced ferroptosis in macrophages. It is expected that the results of this project will provide a novel mechanism(s) for the death of macrophages caused by HIV-1 infection and some new understandings of pathogenesis of HIV-1 infection. More importantly, it is expected to provide a new strategy for the elimination of HIV-1-infected macrophages as a viral reservoir of HIV.