Unraveling the molecular link between HIVAIDS and cancer

我们的无偏蛋白质组学质谱分析和随后的生化分析表明，Plk4通过其c端隐polo-box结合到细胞支架蛋白VprBP的c端酸性结构域（1401-1507）。引人注目的是，HIV-1 Vpr与VprBP的WD40结构域（1003-1400）结合，极大地增强了VprBP- plk4的相互作用，诱导了Vpr-VprBP- plk4复合物的形成。这三种蛋白都与中心体共定位，三元复合物的形成似乎增加了plk4介导的中心粒复制。与这些发现一致，VprBP通过稳定其中心粒相关状态而不是诱导其蛋白酶体降解来促进Plk4的功能，正如在Vpx-VprBP-SAMHD1复合物和其他细胞靶标中所观察到的那样。这些数据表明，当细胞被HIV-1感染时，Vpr可能在生理条件下通过形成Vpr- vprbp -Plk4复合物来改变Plk4的功能，并诱导Plk4依赖的中心粒过度复制，这是一种导致非整倍体和癌症的细胞事件。结构上相关的HIV-2 Vpx不能与VprBP和Plk4相互作用，表明HIV-1 Vpx诱导事件的特异性。基于这些观察，我们假设HIV-1 Vpr可以通过劫持细胞Plk4-VprBP复合物直接改变基因组稳定性并促进癌变。进一步的研究计划在动物模型中使用hiv -1易感细胞和组织来确定三元Vpr-VprBP-Plk4复合物在生理相关条件下的作用。这项研究可能揭示出HIV/AIDS与其合并症癌症的病因直接联系的机制。此外，它可能为理解HIV-1感染者癌症风险增加提供一个新的范例。调查HIV诱导的合并症是NIH指定的四个HIV/AIDS研究重点之一。这项研究旨在直接解决hiv -1相关的癌症合并症。我们在研究HIV蛋白如何与细胞靶标相互作用以及使用各种生化和基于结构的分析改变细胞生理方面获得了丰富的经验。研究SARS-CoV-2 （COVID-19）识别其人类细胞表面受体的方式，并分离破坏这一事件的小分子抑制剂，对于干预病毒进入宿主细胞至关重要。COVID-19刺突蛋白（S蛋白）与人细胞外受体ACE2之间异常高亲和力的相互作用是COVID-19大流行的基础。我们正在寻求利用膜蛋白友好的脂质双分子平台建立特异性的COVID-19 S蛋白- ace2相互作用陷阱，以分离和开发阻止COVID-19进入宿主细胞的小分子抑制剂。

Our unbiased proteomic mass spectrometry and subsequent biochemical analyses showed that Plk4 binds to the C-terminal acidic domain (1401-1507) of a cellular scaffold protein, VprBP, via its C-terminal cryptic polo-box. Strikingly, HIV-1 Vpr, which binds to the WD40 domain (1003-1400) of VprBP, greatly enhanced the VprBP-Plk4 interaction and induced the formation of the Vpr-VprBP-Plk4 complex. All three proteins colocalized to centrosomes and the formation of the ternary complex appeared to augment Plk4-mediated centriole duplication. Consistent with these findings, VprBP promoted Plk4 function by stabilizing its centriole-associated state rather than inducing its proteasomal degradation, as was observed for the Vpx-VprBP-SAMHD1 complex and other cellular targets. These data suggest that, when cells are infected with HIV-1, Vpr may alter Plk4's function by forming the Vpr-VprBP-Plk4 complex under physiological conditions and induce Plk4-dependent centriole overduplication, a cellular event causing aneuploidy and cancer. A structurally related HIV-2 Vpx failed to interact with VprBP and Plk4, indicating the specificity of HIV-1 Vpr-induced events. Based on these observations, we postulate that HIV-1 Vpr can directly alter genomic stability and facilitate carcinogenesis by hijacking the cellular Plk4-VprBP complex. Additional studies are planned to determine the role of the ternary Vpr-VprBP-Plk4 complex under physiologically relevant conditions, using HIV-1-susceptible cells and tissues in animal models. This research could shed light on the mechanism that could directly link HIV/AIDS to the etiology of its comorbid cancers. Furthermore, it may offer a new paradigm in understanding the increased cancer risk in people living with HIV-1. Investigating HIV-induced comorbidities is one of the four designated NIH HIV/AIDS research priorities. This research is designed to directly address HIV-1-associated cancer comorbidities. We have gained an enriched experience in studying how HIV proteins interact with cellular targets and alter cell physiology using various biochemical and structure-based analyses. Investigation into the way in which SARS-CoV-2 (COVID-19) recognizes its human cell surface receptor and isolation of small molecular inhibitors that disrupt this event would be critical for the intervention of viral entry into host cells. The exceptional high-affinity interaction between the COVID-19 spike protein (S protein) and the human extracellular receptor, ACE2, underlies the widespread pandemic of COVID-19. We are seeking to establish a specific COVID-19 S protein-ACE2 interaction trap using a membrane protein-friendly lipid-bilayer platform to isolate and develop small molecule inhibitors against COVID-19 entry into host cells.